Pauline Ferraris
email: pauline.ferraris@gmail.com

Sineewanlaya Wichit

Nadège Cordel

Dorothée Missé

Human host genetics and susceptibility to ZIKV infection

Keywords:

Managing emerging infectious diseases is a current challenge in the fields of microbiology and epidemiology. Indeed, among other environmental and human-related factors, climate change and global warming favor the emergence of new pathogens. The recent Zika virus (ZIKV) epidemic, of which the large and rapid spread surprised the scientific community, is a reminder of the importance to study viruses currently responsible for sporadic infections. Increasing our knowledge of key factors involved in emerging infections is essential to implement specific monitoring that can be oriented according to the pathogen, targeted population, or at-risk environment. Recent technological developments, such as high-throughput sequencing, genome-wide association studies and CRISPR screenings have allowed the identification of human single nucleotide polymorphisms (SNPs) involved in infectious disease outcome. This review focuses on the human genetic host factors that have been identified and shown to be associated with the pathogenesis of ZIKV infection and candidate SNP targets.

Introduction

ZIKV is an emerging arthropod-born virus (Arbovirus) belonging to the genus Flavivirus of the Flaviviridae family that was not considered to be a public-health priority due to only sporadic cases being reported until 2007. At that time, a large epidemic was reported on Yap Island, in which nearly 75% of the population was infected with the virus [START_REF] Duffy | Zika virus outbreak on Yap Island, Federated States of Micronesia[END_REF], followed by several outbreaks reported in French Polynesia, New Caledonia, Easter Island, and the Cook Islands in 2012, indicating rapid spreading of the virus in the Pacific until 2014 [START_REF] Musso | Rapid spread of emerging Zika virus in the Pacific area[END_REF]. These outbreaks were also associated with more severe ZIKV infection-related symptoms such as neurological disorders like Guillain Barré syndrome, which incidence unexpectedly increased by 20 fold [START_REF] Oehler | A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus[END_REF].

In 2015, the ZIKV epidemic was declared a public-health emergency when it reached the American continent, where an estimated 400,000-1.5 million cases of autochthonous transmission of the virus was reported in Brazil. It has since been associated with imported cases of ZIKV infection, notably in Europe, indicating rapid spreading of the virus worldwide [START_REF] Zammarchi | Association of CD1 and FcγR gene polymorphisms with Guillain-Barré syndrome susceptibility: a meta-analysis[END_REF]. This outbreak raised major concerns about the pathogenicity of ZIKV, as severe neurological complications in fetuses, neonates, and adults have been shown to be associated with the infection [START_REF] Cao-Lormeau | Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a casecontrol study[END_REF][START_REF] Mlakar | Zika virus associated with microcephaly[END_REF][START_REF] Baud | An update on Zika virus infection[END_REF]Ferraris et al., 2019b).

An exceptional effort has been made by the scientific community to characterize the interaction between this virus and its target cells, in particular, to better understand the viral pathogenicity to aid healthcare systems in managing the epidemic [START_REF] Hamel | Biology of Zika virus infection in human skin cells[END_REF][START_REF] Baud | An update on Zika virus infection[END_REF][START_REF] Morris | Zika virus as an emerging neuropathogen: mechanisms of neurovirulence and neuroimmune interactions[END_REF][START_REF] Christian | Pathophysiology and mechanisms of Zika virus infection in the nervous system[END_REF]Ferraris et al., 2019b). ZIKV possesses a positive single-stranded RNA that encodes a polyprotein precursor that is processed by cellular and viral proteases to yield the three structural proteins: the capsid (C), the precursor of membrane (prM), and the envelop (E), followed by seven nonstructural proteins: NS1 to NS5. The African and Asian ZIKV strains have been extensively studied [START_REF] Wichit | Chikungunya and Zika viruses: co-circulation and the interplay between viral proteins and host factors[END_REF]. Due to their genetic difference, it has been shown that the two ZIKV lineages differentially infect and lyse human placental trophoblast [START_REF] Sheridan | African and Asian strains of Zika virus differ in their ability to infect and lyse primitive human placental trophoblast[END_REF]. The prM protein is involved in ZIKV-mediated neuro-pathogenicity [START_REF] Nambala | Role of Zika virus prM protein in viral pathogenicity and use in vaccine development[END_REF]. In fact, it has been demonstrated that the higher neurovirulence of African strains could be linked to differences in ten amino acid residues in the prM proteins of the two ZIKV strains [START_REF] Nakayama | Neuroinvasiveness of the MR766 strain of Zika virus in IFNAR-/-mice maps to prM residues conserved amongst African genotype viruses[END_REF]. African strains also display higher transmissibility and fetal pathogenicity than Asian strains [START_REF] Aubry | Recent African strains of Zika virus display higher transmissibility and fetal pathogenicity than Asian strains[END_REF]. The antiviral response elicited against the two strains upon infection of human neural progenitors and astrocytes could also contribute to the higher neurovirulence of the African strains [START_REF] Simonin | Zika virus strains potentially display different infectious profiles in human neural cells[END_REF][START_REF] Hamel | African and Asian Zika virus strains differentially induce early antiviral responses in primary human astrocytes[END_REF].

Many species of Aedes mosquito can transmit ZIKV, including Ae. aegypti and albopictus, which can be found in south of Europe. The Aedes genus is dispersed across three continents (Asia, Africa, and the Americas) in predominantly tropical areas, but has been increasingly spreading, particularly in the Northern regions of the Americas, Europe, and China [START_REF] Kraemer | The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus[END_REF]. Several studies have been performed to evaluate the ability of Aedes mosquitoes to transmit ZIKV. A total of 13 Aedes species have been identified as ZIKV potential vectors including Aedes [START_REF] Epelboin | Zika virus: An updated review of competent or naturally infected mosquitoes[END_REF][START_REF] Zhou | Susceptibility and interactions between Aedes mosquitoes and Zika viruses[END_REF].

The threat posed by ZIKV can be expected to be the same as that of Chikungunya and Dengue virus due to similar clinical symptoms and a similar distribution [START_REF] Musso | Zika virus: following the path of dengue and chikungunya?[END_REF]. ZIKV infection is characterized by fever, rash, arthralgia, and conjunctivitis in infected individuals. However, the biggest concern about ZIKV infection is the development of neurological disorders, such as microcephaly and congenital Zika syndrome (CZS), in newborns [START_REF] Mlakar | Zika virus associated with microcephaly[END_REF].

A better understanding of the cellular mechanisms involved in ZIKV pathogenesis is crucial for the identification of potential single nucleotide polymorphisms (SNPs) as susceptibility factors for the infection. Many studies have identified key anthropic factors in the emergence of viruses, such as ecological modifications and human societal behavior. However, due to the diversity of human genetics no one has been able thus far to determine whether human genetic polymorphisms may be involved in susceptibility to ZIKV infection. Since the large outbreak of ZIKV infection in Brazil, the scientific community has unraveled much about the cellular and molecular mechanisms involved in the infection [START_REF] Baud | An update on Zika virus infection[END_REF]Ferraris et al., 2019b). Moreover, recent advances in human genome sequencing have led to improvements in genome-wide association studies (GWAS) over the last 10 years. These studies attempt to correlate human genetic variants (SNPs) with phenotypic features (symptoms, treatment efficacy, disease, etc.). Thus, the identification of key cellular factors and GWAS results should allow us to determine potential genetic factors involved in the susceptibility of humans to ZIKV infection. In the current review, we focus on the human genetic factors that may be associated with susceptibility to ZIKV infection.

Cellular susceptibility: cell entry and nervous system tropism

Several studies have determined the cell types that can be infected by ZIKV and the cellular mechanisms involved [START_REF] Agrelli | ZIKA virus entry mechanisms in human cells[END_REF]. Many cell types can be infected by ZIKV, but the main concern in human ZIKV infection is those that are associated with the nervous system, reproductive tract, and maternofetal barrier and their role in the pathogenicity and/or transmission of the virus. Like many other flaviviruses, ZIKV uses a member of the C-type lectin receptor family (DC-SIGN), cellular lipid receptors (TIM, TAM), clathrin-mediated endocytosis, GAG, NMR, and endosome-lysosome processes to enter cells [START_REF] Agrelli | ZIKA virus entry mechanisms in human cells[END_REF]. Thus, all genes involved in these mechanisms can affect ZIKV infectivity and their activity may be influenced by human genetic polymorphisms. Although AXL has been shown to be an essential ZIKV entry factor [START_REF] Hamel | Biology of Zika virus infection in human skin cells[END_REF][START_REF] Meertens | Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses[END_REF], genetic alteration of this gene appears to have no effect on ZIKV infection in mice [START_REF] Wang | Axl is not an indispensable factor for Zika virus infection in mice[END_REF][START_REF] Wells | Genetic ablation of AXL does not protect human neural progenitor cells and cerebral organoids from Zika virus infection[END_REF]. These results highlight the diversity of ZIKV entry mechanisms according to cell type. A recent genome-wide CRISPR screen study identified two V-ATPase component genes (ATP6V1F, ATP6V1C1) involved in endosome-lysosome pathways, of which their mutation led to reduced ZIKV infection in human neural progenitor cells (hNPCs) [START_REF] Li | Genome-wide CRISPR screen for Zika virus resistance in human neural cells[END_REF]. These results however are yet to be validated in animal models to evaluate the importance of these gene mutations in global ZIKV infection. Another study used human neuroprecursor cells (hNPC) cells from dizygotic twins exposed to ZIKV during their mother's pregnancy where one child developed CZS while the other did not [START_REF] Amaral | Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins[END_REF]. This case-control sample represented a rare opportunity to test the genetic contribution to the outcome of ZIKV infection by comparing in vitro gene expression of ZIKV infected hNPCs (generated by the induced-pluripotent cell technology) [START_REF] Caires-Júnior | Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells[END_REF]. They first showed that hNPCs from the CZS-affected child were more susceptible to ZIKV infection than those from the non-affected child. Then, they showed differential expression of genes involved in the mTOR inhibition pathway (DDIT4L), Wnt signaling (LHX2, EGR2, SFRP2, WNT7A), and FOX1G1 to be particularly involved in numerous cellular processes, such as cell growth, proliferation, survival, and embryonic development, all associated with microcephaly syndrome [START_REF] Caires-Júnior | Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells[END_REF]. However, it is not known whether these genes are directly or indirectly linked to the pathogenicity. It will be informative to compare the sequences of these genes between the twins (dizygotic and monozygotic) to potentially identify key mutations. The same groups also investigated differential gene expression in infected trophoblasts of the dizygotic twins under the same conditions [START_REF] Amaral | Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins[END_REF]. They did not observe significant differences in gene expression related to candidate attachment factors. Most flaviviruses, such as Dengue virus (DENV), West Nile virus (WNV), and ZIKV, share similar tropism and a similar replication cycle. Therefore, GWAS studies performed on other flaviviruses could help to identify potential polymorphisms associated with susceptibility to ZIKV infection. GWAS studies of DENV infection have identified several human genetic factors associated with the severity of infection [START_REF] Khor | Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1[END_REF][START_REF] Sierra | OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans[END_REF]Xavier-Carvalho et al., 2017a, 2017b), which may also affect ZIKV infection. For example, SNPs have been identified in the promoter sequence of the DC-SIGN gene (CD209) that have been shown to be associated with a predisposition to Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS) [START_REF] Wang | DC-SIGN (CD209) promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation[END_REF]. As ZIKV also uses the DC-SIGN receptor to enter cells, this polymorphism may also lead to a predisposition to ZIKV susceptibility.

Innate immunity

Innate immunity is a key cellular mechanism in the control of the outcome of viral infections, as it represents the first barrier. Although controlled moderate activation of innate immunity can quickly control the infection, a stronger immune response can lead to pathogenic effects. Indeed, when the virus enters the cells it is recognized by various pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). These activate the expression of molecules, such as interferon (IFN), which also leads to the expression of interferon-stimulated genes (ISGs). Thus, any functional mutation in one of these genes could affect the immune response and, thus, the infection outcome and pathogenicity. The specific innate immune response to ZIKV has been investigated in many studies and the IFN type I and III pathways appear to be crucial for the early steps of controlling the infection [START_REF] Hamel | Biology of Zika virus infection in human skin cells[END_REF][START_REF] Lazear | A mouse model of Zika virus pathogenesis[END_REF][START_REF] Bayer | Type III Interferons produced by human placental trophoblasts confer protection against Zika virus infection[END_REF][START_REF] Grant | Zika virus targets human STAT2 to inhibit type I interferon signaling[END_REF][START_REF] Jagger | Gestational stage and IFN-λ signaling regulate ZIKV infection in utero[END_REF][START_REF] Baud | An update on Zika virus infection[END_REF]Ferraris et al., 2019aFerraris et al., , 2019b)). A recent study involving ZIKV-infected pregnant women and newborn babies showed that the rs3775291 SNP in the mother's TLR3 gene, activated by viral RNA, is associated with the occurrence of CZS [START_REF] Santos | Association between Zika virus microcephaly in newborns with the rs3775291 variant in toll-like receptor 3 and rs1799964 variant at tumor necrosis factor-α gene[END_REF]. This SNP was already shown to be associated with other viral infections [START_REF] Verma | Toll like receptor 3 and viral infections of nervous system[END_REF]. They also identified the rs1799964 SNP in the newborn's gene for TNFα, a cytokine involved in inflammation, that also appears to be associated with severe microcephaly [START_REF] Santos | Association between Zika virus microcephaly in newborns with the rs3775291 variant in toll-like receptor 3 and rs1799964 variant at tumor necrosis factor-α gene[END_REF]. IFN molecules belong to the cytokine class and are released in response to the presence of pathogens. Each IFN type (I, II and III) can differentially activate the JAK/STAT pathway by interacting with their specific receptors, leading to the expression of many genes involved in antiviral responses. Several mouse genetics studies have also highlighted roles for specific genes involved in the IFN pathway (STAT proteins, IFN receptors, ISGs, etc.) and associated with susceptibility or resistance to ZIKV infection [START_REF] Manet | Host genetic control of mosquito-borne Flavivirus infections[END_REF]. It is now important to identify the polymorphisms of these genes that are related to ZIKV pathogenicity.

Several polymorphisms in genes known to be part of the response against other members of the Flaviviridae family have been identified. Indeed, polymorphisms have been described for several genes, such as CLEC5A (rs1285933), inducing expression of the proinflammatory cytokine; OAS1 (rs10774671, rs 34137742), involved in viral RNA degradation; and TNFα (rs1800629) for WNV and DENV infections [START_REF] Mashimo | A nonsense mutation in the gene encoding 2 ′ -5 ′ -oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice[END_REF][START_REF] Manet | Host genetic control of mosquito-borne Flavivirus infections[END_REF]Xavier-Carvalho et al., 2017b). Type III IFNs (IFN-λ1 (IL29), IFN-λ2 (IL28A), IFN-λ3(IL28B), and more recently IFN-λ4), appear to play a determinant role in the innate immune response against RNA viruses. The recently discovered IFN-λ3 (rs12979860 C/T) and IFN-λ4 (rs368234815 TT/-G) polymorphisms have been shown to affect the outcome of hepatitis C virus (HCV) infection [START_REF] Ge | Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance[END_REF][START_REF] Suppiah | IL28B is associated with response to chronic hepatitis C interferonα and ribavirin therapy[END_REF][START_REF] Tanaka | Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C[END_REF]Prokunina-Olsson et al., 2013;[START_REF] Bibert | IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction[END_REF]. Although the expression of IFN-λ4 is very low during viral infection, this protein appears to play a crucial role in HCV clearance and the resistance to IFN-α treatment, showing a strong phenotype associated with the polymorphism (Prokunina-Olsson et al., 2013;[START_REF] Ferraris | Cellular mechanism for impaired hepatitis C virus clearance by interferon associated with IFNL3 gene polymorphisms relates to intrahepatic interferon-λ expression[END_REF]. Several studies have also suggested an association between this polymorphism and tick-borne viruses [START_REF] Barkhash | Association of IL28B and IL10 gene polymorphism with predisposition to tick-borne encephalitis in a Russian population[END_REF] and Coronavirus [START_REF] Hamming | Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses: recombinant IFNλ4 is antiviral[END_REF] infection, but its impact on other RNA viral infections has been dispraised. HCV belongs to the Flaviviridae family, which also include arbovirus such as ZIKV, DENV, yellow fever virus (YFV), and WNV. Therefore, it is possible that this polymorphism could affect other viruses of this family as well. Indeed, IFN-λ4 appears to act as a negative regulator of type I IFN activation, which could improve or decrease the efficiency of the immune response, depending on the pathogen [START_REF] Ferraris | Cellular mechanism for impaired hepatitis C virus clearance by interferon associated with IFNL3 gene polymorphisms relates to intrahepatic interferon-λ expression[END_REF][START_REF] Obajemu | IFN-λ4 attenuates antiviral responses by enhancing negative regulation of IFN signaling[END_REF]. The loss of IFN-λ4 expression confers protection against HCV infection, probably due to virus/host adaptation. However, the expression of IFN-λ4 could have different effects in the context of other RNA viral infections, which is yet to be investigated (Prokunina-Olsson et al., 2013;[START_REF] Booth | Loss of function of the new interferon IFN-λ4 may confer protection from hepatitis C[END_REF][START_REF] Ferraris | Cellular mechanism for impaired hepatitis C virus clearance by interferon associated with IFNL3 gene polymorphisms relates to intrahepatic interferon-λ expression[END_REF]. This polymorphism is specifically distributed throughout the world according to country and ethnicity, more particularly between Africa and Asia. The loss of IFN-λ4 expression appears to have been associated with selection pressure during human and viral evolution [START_REF] Wack | Guarding the frontiers: the biology of type III interferons[END_REF][START_REF] Ansari | Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus[END_REF]. The ethnic distribution of polymorphisms in southern countries and the speared of arboviruses suggest that the polymorphism of IL28B involved in innate immunity could be a cellular host factor associated with viral outbreaks, such as that of ZIKV.

Adaptative immunity

An effective and specific adaptative immune response is also primordial for the control of viral infection. However, a dysfunctional or over/under-activated response can lead to symptoms associated with the infection. Thus far, no SNPs associated with the adaptative immune response against ZIKV have been identified. Several human genetic polymorphisms have already been characterized for other flaviviruses and need to be investigated in the context of ZIKV infection. A major concern of ZIKV infection is the possibility that the infection can lead to antibody-dependent enhancement (ADE), as observed for DENV, or be enhanced by ADE from a prior DENV infection. ADE is caused by nonneutralizing antibodies that are produced during the infection. They form an immunocomplex with the virus that can be internalized by Fc- receptor-bearing cells [START_REF] Bournazos | The role of IgG Fc receptors in antibodydependent enhancement[END_REF][START_REF] Littaua | Human IgG Fc receptor II mediates antibodydependent enhancement of dengue virus infection[END_REF]. Despite the fact that ZIKV infection appears to not lead to the production of such antibodies, it appears that prior DENV infection and DENV-ADE production can enhance ZIKV infection [START_REF] Castanha | Dengue virus (DENV)-specific antibodies enhance Brazilian Zika virus (ZIKV) infection[END_REF][START_REF] Khandia | Modulation of dengue/Zika virus pathogenicity by antibodydependent enhancement and strategies to protect against enhancement in Zika virus infection[END_REF]. The relationship between ADE production and the outcome of ZIKV infection is still debated due to contradictory results and likely multifactorial mechanisms. For example, DENV serotypes appear to play a key role in the production of ADE [START_REF] Guzman | Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection[END_REF][START_REF] Khandia | Modulation of dengue/Zika virus pathogenicity by antibodydependent enhancement and strategies to protect against enhancement in Zika virus infection[END_REF] and human genetic factors may be involved in the pathogenetic effects of ADE in second infections. For example, several FcgRII gene polymorphisms have been identified, in particular, the SNP rs1801274, which has been shown to be associated with the severity of DENV symptoms [START_REF] Loke | Susceptibility to dengue hemorrhagic fever in Vietnam: evidence of an association with variation in the vitamin d receptor and Fc gamma receptor IIa genes[END_REF][START_REF] Sánchez | Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcγRIIa polymorphism[END_REF]García et al., 2011b;[START_REF] Fang | Genetic polymorphisms of molecules involved in host immune response to dengue virus infection[END_REF][START_REF] Dettogni | Single nucleotide polymorphisms in immune system genes and their association with clinical symptoms persistence in dengue-infected persons[END_REF] depending on the ethnicity of the population [START_REF] Noecker | Contrasting associations of polymorphisms in FcγRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population[END_REF]. Thus, rs1801274 could be a determinant factor for the outcome of ZIKV infection for those who had a prior DENV infection or vice versa. In addition, studies of GBS patients and the use of meta-analysis, have reported that CD1E and FcgRIIA genes polymorphism are associated with susceptibility to GBS and ZIKV infection-related symptoms [START_REF] Van Der Pol | IgG receptor IIa alleles determine susceptibility and severity of Guillain-Barre syndrome[END_REF][START_REF] Wu | The effect of TNF-alpha, FcγR and CD1 polymorphisms on Guillain-Barré syndrome risk: evidences from a meta-analysis[END_REF]Zhang et al., 2018). When a virus infects a cell, it is degraded into small peptides that are presented on the cell surface through major histocompatibility complex (MHC) receptors to be recognized by lymphocytes. The locus for MHC receptors is highly polymorphic, especially that for MHC class II. MHC class II genes have been shown to be associated with the outcome of many viral infections, such as WNV disease and its severity [START_REF] Lanteri | Association between HLA class I and class II alleles and the outcome of West Nile virus infection: an exploratory study[END_REF]. Several studies have explored the potential genetic contribution of the MHC genes and revealed several significant SNPs associated with the symptoms of WNV infection and neuroinvasion [START_REF] Lanteri | Association between HLA class I and class II alleles and the outcome of West Nile virus infection: an exploratory study[END_REF][START_REF] Manet | Host genetic control of mosquito-borne Flavivirus infections[END_REF][START_REF] Sarri | Genetic contribution of MHC class II genes in susceptibility to West Nile virus infection[END_REF]. Such studies also identified MHC class I and II SNPs closely associated with the severity of DENV infections (DHF/DSS) [START_REF] Stephens | HLA and other gene associations with dengue disease severity[END_REF]García et al., 2011a;[START_REF] Fang | Genetic polymorphisms of molecules involved in host immune response to dengue virus infection[END_REF]. These studies thus represent an interesting means to also determine potential MHC polymorphisms associated with the outcome of ZIKV infection. In addition, another polymorphism in the CTLA4 lymphocyte receptor has been shown to be associated with DENV disease [START_REF] Fang | Genetic polymorphisms of molecules involved in host immune response to dengue virus infection[END_REF]. This receptor is expressed on activated lymphocyte T cells to downregulate the immune response through the transmission of an inhibitory signal. Indeed, the SNP Exon 1 + A/G polymorphism in CTLA4 genes appears to enhance DENV-associated symptoms [START_REF] Fernández-Mestre | Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases[END_REF]. Moreover, a study showed that the combination of this SNP with the TGFβ1 (which controls immune cell growth, proliferation, and differentiation) SNP -509 CC is associated with DHF in the Taiwanese population [START_REF] Chen | Combination of CTLA-4 and TGFβ1 gene polymorphisms associated with dengue hemorrhagic fever and virus load in a dengue-2 outbreak[END_REF]. Further studies are needed to evaluate the impact of CTLA4 and TGFβ1 polymorphisms in other flavivirus infections, such as ZIKV, and on other populations.

Conclusion

Viral propagation and pathogenicity depend on multiple pathways. The identification of key cellular factors and their polymorphisms will allow to define a panel of genes strongly involved in pathogenicity and transmission, making it possible to better prevent infection and improve patient outcome. Studies have revealed a strong disequilibrium between ethnicity and population for susceptibility to flavivirus infection. This review summarizes susceptible genes and SNP targets associated with the innate and adaptive immune responses against ZIKV as shown in Fig. 1 and Table 1. It is therefore crucial to investigate these polymorphisms in various populations. These results could at least partially explain the emergence and propagation of ZIKV and other flaviviruses. Because the virus also shows genetic variability, it is important to take into account such factor in association with human genetic polymorphisms and identify possible combinations of mutations that play a role in the symptoms of ZIKV infection. The worldwide propagation of ZIKV has been highlighted by the occurrence of severe symptoms, revealing perhaps just the tip of the iceberg. There is clearly an urgent need to understand both the overall spatial and temporal pattern of intercontinental transmission of ZIKV, which should be integrated with new knowledge on the evolution of epidemic lineages.

Fig. 1 .

 1 Fig. 1. Summary of susceptible genes and SNP targets associated with pathogenicity and transmission of Zika virus infection in innate and adaptive immunity of humans. Star: susceptible gene and its SNP target (Modified from Wichit et al., 2021).

Table 1

 1 SNP genes associated with ZIKV and Flavivirdae infection pathogenicity.

		Cell susceptibility		Innate immunity		Adaptative immunity
	Zika				TLR3	rs3775291	Verma and Bharti
							(2017)
					TNFa	rs1799964	Santos et al. (2019)
	Candidate SNP	PLCE1	rs3740360	Dang et al. (2014), Khor	CLEC5A	rs1285933	Xavier-Carvalho	FcgRII	rs1801274	Loke et al. (2002),
	from other			et al. (2011), Whitehorn			et al. (2017b)			García et al.
	Flaviviridae			et al. (2013)						(2011b)
			rs3765524					CTLA4	Exon 1 +	Fang et al. (2012),
									A/G	Fernández-Mestre
										et al. (2009)
		MICB	rs3132468	Dang et al. (2014), Khor	OAS1	rs10774671; rs	Lim et al. (2009)	TGFb1	509 CC	Chen et al. (2009)
				et al. (2011), Whitehorn		34137742
				et al. (2013)
		DC-			OASL	rs3213545	Yakub et al. (2005)
		SIGN
		CD209	rs4804803	Sakuntabhai et al. (2005),	TNFa	rs1800629	Fernández-Mestre
				Wang et al. (2011),			et al. (2004)
				Xavier-Carvalho et al.
				(2017a)

Acknowledgments

We thank Dr. Thanyakorn Rongsawat for technical assistance. All the authors included in this manuscript are responsible for its contents and have agreed to its publication. Authors don't have any financial or personal conflict of interest. The results of this manuscript have not been published elsewhere.

Funding

This work was supported by grants from the French National Research Agency (ANR-17-CE15-00029 and ANR-16-IDEX-0006).


Keywords: Democracy, Voting, Equality, Liberty, Duties, Rights 1

Should voting be compulsory? A surprising number of people seem to believe that it should, and that countries like Britain, which have never had compulsion, ought to adopt it. 1 As is common with such things, the arguments are a mixture of principle and political calculation, reflecting the idea that compulsory voting is morally right and that it is likely to prove politically beneficial. This article casts a sceptical eye on both types of argument. It seeks to show that the idea of a moral duty to vote is far less clear than proponents of compulsion believe, as is the case for turning a moral obligation into a legal one. It also suggests that the evidence of beneficial consequences from compulsion is weak. Hence, I show, while there are good reasons to worry about declining voter turnout in established democracies, and to worry about inequalities of turnout as well, the case for compulsory voting is not proven.

As we will see, the principled arguments for compulsion tend to turn on the claim that compulsion is justified as a way to combat the free-riding of non-voters on voters. Such free-riding, it is claimed, is an unjustified exploitation of the provision of a collective gooda democratic party systemand, unless curbed, is likely to undermine it. The pragmatic arguments are that compulsion is necessary to combat inequality in voting, which disadvantages the political left, because the propensity to vote is, overwhelmingly, characteristic of the more established and better educated members of society. 1 The key paper which sparked contemporary interest in the topic is Lijphart, 1997. A recent British argument for CV is Keaney and Rogers, 2006, available online at www.ippr.org/publicationsandreports .

Abstract:

Should voting be compulsory? Many people believe that it should, and that countries, like Britain, which have never had compulsion, ought to adopt it. As is common with such things, the arguments are a mixture of principle and political calculation, reflecting the idea that compulsory voting is morally right and that it is likely to prove politically beneficial. This article casts a sceptical eye on both types of argument. It shows that compulsory voting is generally unjustified although there are good reasons to worry about declining voter turnout in established democracies, and to worry about inequalities of turnout as well.

Preliminaries

The term 'compulsory voting' can be a bit misleading, at least in democracies, where the secret ballot obtains. Because of secrecy, it is impossible to verify whether or not anyone has cast a legally valid ballot. Consequently, compulsory voting generally means compulsory turnout or, as some call it, compulsory participation. 2 However, because the purpose of compulsion is to get people to vote, rather than just to turn out or to participate in some generic way, talk of compulsory voting strikes me as less misleading than these other terms, and is the term that I will be using here.

The case for compulsory voting can be reconstructed in six steps which highlight its connections to democratic theory and practice. Not all countries with compulsory voting are democratic, nor are all arguments in its favour. [START_REF] Lopez | International IDEA[END_REF] However, the ones that I am concerned with seek to show that compulsory voting is consistent with democratic norms, institutions and values and may, indeed, be required by them. Not every proponent of compulsory voting will make each of the steps in the argument below, nor make them in the order in which I present them. However, this reconstruction is meant to illuminate the moral and political concerns which animate democratic arguments for compulsory voting, and to illuminate their logical connections. These arguments have, 2 Arend Lijphart refers to compulsory turnout in Lijphart, 1997. Sarah Birch refers to compulsory participation in Birch, 2007. This paper is drawn from her book, Full Participation: A Comparative Study of Compulsory Voting, which is due to be published in 2008. [START_REF] Lopez | International IDEA[END_REF] Examples of democracies with compulsory voting include Australia, Belgium, Luxembourg, Cyprus and Greece; examples of nondemocratic instances of compulsory voting are Egypt and Singapore. Australia introduced compulsion in 1924, and surveys suggest that about three quarters of the electorate are satisfied with the practice. See Hill, 2007, 4. Compulsory voting was introduced in Belgium with the introduction of universal male suffrage. Not only did women then lack the vote, but the male franchise was unequal as additional votes were available based on one's education and status.

predominantly, been advanced by those who support social democratic policies, broadly understood. So, I have followed Arend Lijphart in supposing that concerns for political equality, as well as political legitimacy, are important to the case for compulsion although, historically, proponents of compulsory voting in Europe seem to have come from the right, rather than the left. (Pilet, 2007) 4

A. THE CASE FOR COMPULSORY VOTING

Step One: Low Turnout is Unequal Turnout Participation in elections is declining in most advanced industrial countries. 5 Lower turnout, moreover, is more unequal turnout and these two facts, taken together, underpin the case for compulsion. 6 Lower turnout seems to threaten the legitimacy of a country's government and electoral system, because it significantly increases the likelihood that governments will reflect a minority, rather than a majority, of registered voters, and of the voting-population, itself. As Ferdinand Mount said, commenting on the report of the Power Inquiry, in Britain, 'when little more than 20% of the electorate has voted for the winning party, as in the United Kingdom general election of May 2005, legitimacy begins to drain away'. He adds, 'If only just over half of us bother to vote at all in national elections and scarcely a third in local elections, the bureaucracy begins to think of elections as a tiresome and increasingly insignificant interruption in its continuous exercise of power. What develops is…'executive democracy' and….more rudely described… "elective dictatorship"'. (Mount, 2006) It is not news that turnout has been declining in most democracies since the Second World War. However, the association of low turnout with unequal turnout may be less well known and its significance less clearly appreciated. For example, in the last two General Elections in Britain the participation gap between manual and non-manual workers more than doubled: from around 5% in 1997 to around 11% in 2005. Likewise, between the 1960s and 2005 the difference in turnout between the top and bottom quartile of earners grew from 7% to around 13%. 7 The results are not dissimilar in other countries, and are particularly pronounced in the United States, where turnout at presidential elections for the college educated can be over 25% higher than that of the population as a whole, while those who lack a high-school diploma are 16% less likely to vote than the general population. (Rose, 2000, 316-7)

Second Step: Unequal Turnout Reflects and Reinforces Social Disadvantage

The fact that lower turnout means increasingly unequal turnout is troubling, because those least likely to turn out are overwhelmingly drawn from the least privileged social groups in a polity. Thus, the IPPR report notes that though 'socio-economic statuswhether measured by income, class or educationis not as significant a factor as age in determining whether a person will vote or not, it has nevertheless become an increasingly 7 These figures can be found on the IPPR's 'Press Release' of May 1, 2006, for its report on compulsory voting. See http://www.ippr.org.uk/pressreleases/?id=2083.

significant factor -at least in the UK. ….although there has been some decline in turnout among all income categories since 1964, the decline is most rapid for those with the lowest income'. (Kearney and Rogers, 12) So, it looks as though those people who do least well in our societies are least likely to vote; and in what seems to be a vicious circle, those least likely to vote are least likely to attract sympathetic attention from politicians eager to get elected or reelected.

So inequalities in turnout are troubling, because they suggest a vicious circle in which the most marginal members of society are further marginalized. 8 Not only that: in so far as these non-voters are more likely to vote for social democratic polities than other people, and particularly likely to benefit from them, inequalities in turnout seem to deprive the left of a significant political constituency and make it easier for the right to get reelected.

Hence, as Lijphart makes plain, social democrats should be particularly concerned about declining voter turnout because it makes it more difficult to elect social democratic governments and, therefore, to pass social democratic legislation or public policies. 9 8 Lijphart, 6 notes that 'the decline in turnout has been accompanied by a "participatory revolution" in Western Europe with regard to more intensive forms of political participation in which class bias is very strong'. 9 Lijphart, 5 cites evidence that 'the left share of the total vote increases by almost one-third of a percentage point for every percentage point increase in turnout". However, in footnote 8, p.5, he refers to a study of the UK, where "high turnout has meant a consistent disadvantage for the conservatives, a modest gain for the Liberals, and no appreciable advantage for Labourbut, of course, a relative advantage for Labour as a result of the Conservatives' disadvantage'. This study is from 1986, and so the results may have been affected by the relative scarcity of Labour victories in the period and might look rather different if one extended the results up to 2005. Now, as it happens, in Britain, as in most other countries, it is age, rather than wealth or income, which is the best predictor of who votes. 10 Interestingly, in Britain, race is not a significant variable in explaining turnout, nor is wealth per se. In so far as they matter to turnout, in other words, it is because they are correlated to age and to the second most important factor to explain turnout, namely, education 11 Indeed, Keaney and Rogers say of age that 'it is the single most significant of socio-demographic factorsmore significant even than socioeconomic status'. (11) The fact that it is age and education, rather than race, income and wealth that directly determine voting, makes it harder to know how troubling disparities in turnout really are. In principle, young people can be expected to have older people who care about them, and who are likely to vote bearing their interests in mind. In practice this may not be the case. In so far as young people are born to young parentswhich is particularly likely if they are relatively uneducated and socio-economically deprivedyoung non-voters may, in fact, have young non-voting parents, family members and friends. In those circumstances, they may well lack anyone amongst those who vote who shares their interests and concerns.

The Third Step: Compulsion is the Best Cure 10 Blais reports that Franklin's 1996 of 22 countries shows that age comes out as the most important socioeconomic variable Blais' own analysis of the Comparative Study of Electoral Systems (CSES) survey of 9 countries confirmed that age and education are the two critical variables, (Blais, 2000, 51-2). 11 Apparently MORI estimates from 2001 suggest that only 39% of 18 -25 year olds voted, compared to 70% of the over 65s. (Keaney and Rogers, 11 and 49-54).

If the first steps in the argument for compulsory voting are, typically, an expression of concern about declining and increasingly unequal turnout, the next step notes that there are a variety of plausible remedies for these problems. However, none seems as immediate, or as effective as compulsion in rectifying both low and unequal turnouts. Thus, while it is common to suggest that registration and voting should be made easier, that voting should take place at weekends, and that more active campaigning of all voters should be promoted, none of these is guaranteed to have any significant effect on turnouts, or on inequality. Such effects, in any case, are likely to be medium to long term. 12 By contrast, compulsory voting has immediate and dramatic effects on turnout, and the results are most dramatic the lower the rate of turnout to begin with. [START_REF]The International Encyclopedia of Elections[END_REF] For example, in the 24 elections since 1946, Australia has average turnout of 94.5%; and in the 19 elections since 1947, Belgium averaged 92.7% turnout. So, compulsion in and of itself can turn around low turnout and, even though it cannot wholly remove inequalities of turnout, it can dramatically lessen these, too.

Fourth Step: Possible Additional Benefits to Compulsion

The next step in the case for compulsory voting is to note that compulsion may have other good effects, beyond immediate and significant increases in turnout.

(Liijphart, 10 -11) It may cut down the cost of campaigns, encourage politicians to 12 Lijphart, 7 quotes 15% as the maximum benefit that registration reform would have in the US, and notes that it is irrelevant to most Western democracies, who have fairly high rates of registration to begin with. Proportional Representation may stimulate turnout by 9-12%, but, as footnote 14, p. 7 makes plain, 'multipartism, which is strongly associated with PR, depresses turnoutthus undoing some of PRs beneficial influence -and..bicameralism lowers turnout as well'. At p. 8 he notes that weekend voting increases turnout by 5 -6 percentage points in first order elections, and in second order European Parliament elections, weekend voting raised turnout by more than 9 percentage points. [START_REF]The International Encyclopedia of Elections[END_REF] Apparently compulsion can raise turnout from 7 --16 percent, even when the penalties for voting are low. (Lijphart, 8) engage with those who are least interested in politics, and it may minimize negative campaigning, as well. The idea behind these potentially attractive features of compulsion is that if everyone has to vote, politicians can largely take turnout for granted, but have an especial interest in ensuring that those who turn out do not vote for the other side. In short, compulsion means that the battle is not, any more, to make sure that your supporters actually get to the polls, or to deter those of your opponents from doing so, (apparently the chief effect of negative campaigns), but to ensure that of those who turn out, as many vote for you as possible. ( Ansolabehere and Iyengar, 1995; Lijphart, 10) Lijphart makes it plain that these benefits are speculative. Unfortunately, the IPPR report treats them as fact, although failing to cite any evidence on their behalf. (Kearney and Rogers, 7)

Fifth Step: No Liberties Violated Because of Turnout/Voting Distinction

The final stages in the argument for compulsion aim to show that there are no significant down-sides to compulsory voting. The first move in this process is to claim that compulsory voting does not violate any significant liberties, because it does not actually force people to vote, as opposed to requiring them to turnout. (Lijphart,11) 14 Most proponents of compulsory voting believe that voters should have the option to vote for "none of the above", although none of them ever discuss what should happen if that option turns out to have the largest share of the vote in an election, or sufficient to turn it 14 Lijphart is interesting in that he seems to believe that there is a right not to vote, by contrast with Wertheimer, and claims that there is a good case to have the option of voting for 'none of the above', that that the right to refuse to accept a ballot 'is an even more effective method to assure that the right not to vote is not infringed'. (Lijphart, 11, Footnote 23) into the major "opposition" party. 15 The IPPR, indeed, notes in a footnote that it would forbid people from campaigning for a "none of the above" option, although explicitly supporting the provision of such an option on the ballot. 16 So, while it is clear that considerably more thought has to go into the deciding what a "none of the above" option entails, and whether it is, in fact, desirable, the core idea is clear: compulsory turnout must be distinguished from compulsory voting, out of concern for civil and political liberties. Compulsory turnout seems to violate no liberties, and so it seems that there can be democratic forms of compulsory voting, and that these can be readily distinguished from authoritarian or totalitarian variants.

Step Six: Non-voters are Free-Riders and Free-Riding is Morally Wrong

The final, and crucial, step in the case for compulsion is the claim that non-voters are free-riding on voters. They are, it is claimed, selfishly benefiting from the public good of a democratic electoral system without doing their part to maintain it. This claim can be found in every argument for compulsory voting, although it is rarely spelled out in any detail. 17 The key idea here is that a democratic electoral system is a public good, in that all citizens get to benefit from it, even if they do nothing to contribute to it. Because it is a public good, it is possible to free-ride, or to enjoy the benefits of that good, without contributing oneself and, indeed, most people will have an interest in doing precisely that.

Non-voters, therefore, can be seen as free-riders, selfishly and immorally exploiting voters. The moral force of this point is two-fold. First, it reinforces the idea that no morally significant liberties are threatened by compulsory turnout and, secondly, it carries the battle into the enemy camp. It is selfish and exploitative to benefit from the efforts of other people without making any effort to contribute. So, far from compulsion being unjustified, or even morally neutral, it seems positively desirable, as a curb on selfish and exploitative behaviour. As Lijphart puts it, 'It must be remembered that nonvoting is a form of free ridingand that free riding of any kind may be rational but is also selfish and immoral. The normative objection to compulsory voting has an immediate intuitive appeal that is not persuasive when considered more carefully'. (Lijphart, 11)

Summary of the Case for Compulsory Voting

The case for compulsory voting, then, is this: that it is the best means we have to combat the twin evils of low turnout and unequal turnout, and to do so with no significant costs. Compulsion has no significant costs, because the compulsion is to turnout, not to vote; and so no liberties of thought, expression or participation are threatened; nor are people treated in any way that is morally unjustified. Moreover, because nonvoters are, essentially, free-riding on the efforts of others, and because a democratic electoral system is an extremely valuable collective good, we are justified in preventing such free-riding, by compulsion if necessary. The justification for compulsory voting, then, is meant to be democratic and to be clearly distinguishable from authoritarian or totalitarian alternatives.

The democratic concerns animating the case for compulsory voting make it attractive even to those, like me, who intuitively find the idea of compulsory voting distasteful. Moreover, as proponents of compulsion rightly point out, compulsory voting is a feature of several democratic countries, and has extraordinary and enduring levels of support in Australiaa country with a reputation for individualism, rather than the reverse. In fact, the democratic case for compulsion can be seen as an effort to make explicit and to systematize the experiences of several democracies.

Nonetheless, I will argue, the democratic case for compulsion has not been made, and is far harder to make than its proponents believe. I will lay out my concerns in five steps, arguing that the supposed benefits of compulsion are more speculative and uncertain than proponents believe, and that compulsion threatens people's freedom and equality in ways they have overlooked.

B. THE CASE AGAINST COMPULSION

Step One: The Evidence The connection between compulsory voting and social democratic politics is more speculative and uncertain than Lijphart suggests. Those paradigmatic instances of social democracy -Sweden,18 Norway 19 and Finlanddo not have compulsory voting and, indeed, appear to suffer from the same worries about declining voter turnout and indifference to the major political parties which trouble countries with more free-market economies, such as the United States and Britain. Moreover, while the Netherlands used to have compulsory voting, one of the reasons given for rejecting it was, precisely, the belief that the practice is undemocratic. (Gratschew, 29) Empirically, therefore, there seems to be little affinity between social democratic politics and compulsory voting. Nor is there any theoretical reason why the link should be tight. Voters do not always vote on their self-interest-for good and ill-so from the fact that social democrats assume that it would be in the interest of the socially disadvantaged to vote 'left' it does not follow that that is how the socially disadvantaged will vote, when they vote. So, with due deference to Lijphart's expertise, I do not share his optimism about the likely voting patterns of current nonvoters. Instead I fear that if voters cannot spontaneously see the case for voting for a social democratic party or its nearest equivalent, the compulsion to turnout is unlikely to make it plainer.

Indeed, the evidence suggests that compulsory voting does nothing other than raise turnoutand there are, in fact, some questions about how far it is better than other means of doing this, too. 20 Recent work suggests that compulsory voting has no noticeable effect on political knowledge or interest, (Engelen and Hooghe, 2007) 21 nor, more surprisingly, any evident effect on electoral outcomes. (Selb and Lachat, 2007) 22 Unfortunately, it also does not seem to force parties to compete for the votes of the poor, the weak or the marginalized, as Lijphart hoped, or even reduce the costs of electoral campaigns. Hence, Ballinger concludes, 'Compulsory turnout does not guarantee inclusiveness; nor does it guarantee political equality'. (Ballinger, 2006, 13) 23 Step Two: the Normative Aspects of Low and Unequal Turnout My second concern with the case for compulsion is that it seems to imply that all forms of low and unequal turnout are ethically troubling, though this is not obviously so.

There is no reason to suppose that people should be equally interested in politics at all times, or that all people should find voting equally satisfactory. 24 Above all, it is morally 20 Helen Margetts notes that moving from First Past the Post to a system of Proportional Representation in Britain would increase turnout by about 12%, which is in line with the 10 -15% increase ascribed to compulsory voting in countries where it has been introduced. ( Margetts, 2006, 29) 21 Ballinger notes that while 'The Australian Election Commission works tirelessly to ensure that the Australian electors are as informed as possible about their system of voting', knowledge about the workings of their political system is low. (Ballinger, 13) 22 Selb and Lachat show is that compulsory voting forces people to vote even if they are uninterested in politics, and have no consistent political beliefs or preferences. Hence, there is no predictable partisan result from the inclusion of such voters in elections. For a discussion of the Polish case, see Czesnik 2007.. 23 Mackerras and McAllister, (1999) 219. Young people enroll far less often than older people: for 18 -24 year olds the estimate is 78% to 93% for the eligible population as a whole. If voting is then estimated based on this figure, turnout is in 1990s would prove to be around 83.7% rather than 96.2% that follows from taking enrollment as the baseline. Needless to say, this is a very significant difference, and suggests a fairly high degree of noncompliance, as well as of inequalities in voting. See footnote 6, p.219 See also Ballinger, pp. 16-18. Ballinger also notes that while Australia made voting compulsory in 1924, Aborigines were only entitled to vote in 1962 and were not compelled to participate until 1983. Even now, their participation rates can be as low as 77.71% even in areas where they are a politically significant minority, and 5% of that 77% are invalid. 24 Gerry Stoker suggests that there is something inherently disappointing and frustrating about democratic politics, precisely because it is difficult and requires one to accommodate the interests of those with whom one disagrees. Indeed, he thinks that unreasonable expectations of personal satisfaction may partly be to blame for political disenchantment in established democracies. (Stoker, 184-194).

and politically important to distinguish amongst different types of non-voters. There may be reasons to be troubled by those who do not vote because they are not particularly excited by any candidates, or because they are disenchanted by their favoured political partyas the failure to vote may point to deep-seated weaknesses in the competitive party system, and in the organization and ideology of the main political parties. But these problems, real as they are, seem far less urgent than those of the people who do not vote because voting and political participation of any form seem as alien and remote as university education, stable, well-paid work, decent housing, safe streets, and respect from other members of society. The difficulty in such cases is to see how compulsory voting will address, rather than exacerbate, the alienation of these non-voters, who are typically the objects, not the subjects, of political debate and policy, and who typically constitute the 'problems' that politicians are competing to solve. 25 This worry seems particularly acute because the evidence does not support Lijphart's hope that compulsory voting will force parties to compete for all sections of the electorate, rather than targeting only a critical subsection. Compulsory voting largely takes the guesswork out of electoral turnout, and this makes it easier to target swing seats or constituencies, and easier to identify the key voter groups within marginal seats, themselves -even under systems of proportional representation. (Ballinger, 16-17) So, even if we abstract from voter dissatisfaction with the electoral choices that they face, and the platforms with which they are presentedboth plausible reasons for political 25 As Irwin and Holsteyn say, 'It is clear ….that many respondents opposed compulsory voting [in the Netherlands in the 1960s] because they were alienated from the political system in general', although compulsory voting seems to have had broad, though weak, support right up until its abolition. (Irwin and Holsteyn, 2005). alienation and low turnoutcompulsory voting seems unlikely to address the profound feelings of political powerlessness and inefficacy that seem to trouble the UK, and other established democracies. The worry, as Ballinger says, is that compulsory voting will exacerbate these feelings of alienation and powerlessness, even as the compulsion to vote removes 'the very indicator which has helped kick-start the current debate about political engagement'. 26 The Third Step: Penalties for Nonvoting and their Enforcement Proponents of compulsory voting tend to say that the penalties for non-voting are, typically, no higher a relatively low fine. According to Ballinger, 'High penalties are often thought not to be appropriate: such penalties disproportionately affect the poor, and can lead to heavy costs on an electoral commission'. ( 11) But even where that is true, it is important to realise that people can, and do, go to prison for failing to pay fines, and that this is the case, as well, for those who fail to pay fines for non-voting.

For example, in 1999 Melissa Manson was sentenced to one day in prison for failing to pay the fines incurred by her failure to vote in the 1993 and 1996 Federal elections. Manson, apparently, believed that there were no candidates worth voting for, and therefore objected both to voting, and to paying the resulting fine, on principle. (Hill, 6 -7 and 17) Before holding that compulsory voting is justified, therefore, we need to be prepared to make criminals of people who do not pay their fines for not votingand need to be confident that doing so is consistent with the democratic values and objectives that animate this case for compulsion. 27 The penalties for not voting in many democracies are fairly slight and the striking thing about countries such as Australia and Belgium is that people still vote although in Belgium fines are rarely enforced, and in Australia, excuses for not voting seem to be readily accepted. 28 But that does not mean that all penalties low. In Italy, non-voters originally had their cards of good conduct marked and people feared that they would lose their chances of civil employment if they did not vote at the many different elections and referenda that were required. Likewise, in Belgium, the penalties on paper are quite severe, although rarely enforced. In principle, failure to vote four or more times within a 15 year period will lead to exclusion from the electoral register for 10 years and, if one is a civil servant, it will also mean disqualification from the chance of promotion. (Gratschew, 27-29) Even now, apparently, people in Italy can be denied places at state childcare facilities, under what is misleadingly called 'the innocuous sanction'. 29 For those whose employment depends on state-funded childcare of various sorts, the mere threat of losing a place would be far more alarming than the prospect of even a hefty fine. 27 Perhaps concerns of this sort explain the recommendation of the 1997 Joint Standing Committee on Electoral Matters, in Australia, that compulsory voting be repealed for federal elections and referenda. It claimed that "if Australia is to consider itself a mature democracy, compulsory voting should now be abolished". Quoted in Hill, 4-5 28 Hill says that in Australia most excuses for not voting are readily accepted, and no documentation is required. (Hill, 12) However, the Australian Electoral Commission successfully fought a freedom of information case in order to prevent the full list of exemptions from being disclosed, so there is not way for citizens to check that exemptions are being fairly granted nor, indeed, that the criteria for exemptions are adequate. Anecdotal evidence for Belgium suggests that people may be unaware that enforcement is rare. 29 Birch notes that until December 1993, Italian law required that the names of non-voters be posted at local municipal offices, (Birch, 10 footnote 13) and 'before the removal of sanctions for non-voting in the mid 1990s, the fact of not having voted was noted on official documents, and there are reports that this may have made it difficult to obtain services such as childcare'. (Birch, 12 footnote 17).

What seems like a trivial penalty to some people, then, is a very grave threat to others; and there is nothing about compulsory voting that means the penalties for non-voting must be trivial.

Step 4: The Right Not to Vote is Not a Trivial One Despite the claims of proponents of compulsory voting, I am not persuaded that the right not to vote is a trivial one, whether we consider 'voting' to mean 'turnout' or something more demanding. 30 The right to abstain, or to refrain from political selfidentification and participation is an important one, symbolically and practically. It captures two ideas that are central to democracy. The first is that government is there for the benefit of the governed, not the other way round. The second is that the duties and rights of citizens are importantly different from those of their representatives, because the latter have powers and responsibilities that the former do not.

Citizens do not owe their government electoral support or legitimacy. This is one reason to doubt that citizens have a duty to vote even though, as Rawls claims, people have a natural duty to support just, or nearly just, institutions. (Rawls, 1971) 31 In some circumstances this natural duty might place citizens under a moral obligation to vote and, even, to vote one way rather than another. For example, if there was a real danger that a 30 Lisa Hill simply says 'The claim that compulsion violates the liberal-democratic principles of choice and freedom is without doubt a valid one. But there are other important liberal-democratic principles at sake here, among them: legitimacy, representativeness, political equality, inclusiveness and minimization of elite power, all of which are served by compulsory voting'. (5) But it remains to be seen how these democratic values are served by forcing people to queue to tick their names off an electoral register or, indeed, to pick up a ballot. 31 Rawls says that '…From the standpoint of the theory of justice, the most important natural duty is that to support and to further just institutions…' (Rawls, 1971 Para. 51, 334) I look at the implications of Rawls' views for Justine Lacroix's 'liberal' justification of compulsory voting in Lever, 2008. racist candidate would be elected in a constituency where one has the vote, one might have a natural duty to vote in favour of the best of the alternatives, however unappealing. Such a natural duty would, I imagine, exist in addition to whatever duties of solidarity and support one has-as a citizen, or as a member of a socially advantaged group -to those who are threatened by such an electoral prospect. Still, it will not be easy to ground a general duty to vote on this natural duty, because in general it is unclear why support for just institutions should take the form of 'electoral participation', rather than anything else. Reasonable people can disagree about the value of political participation relative to other forms of social participation and support, and even those who value political participation may disagree about the value of voting, compared to other forms of political activity. So it is doubtful that the natural duty to support just institutions can justify legal duties to vote, even though it may sometimes give us morally compelling reasons to vote in some elections.

Democratic conceptions of freedom and equality also cast doubt on the idea that citizens have a general duty to vote that should be legally enforced. Differences in power and responsibility between citizens and legislators properly affect the rights and duties of each. Party discipline may justly require legislators to vote, and to vote one way rather than another. 32 Democratic conceptions of responsibility, accountability and equality may also require legislators to vote openly, rather than secretly, although legislators, like 32 Birch reports that in France public officials are required to vote in elections to fill the Senate, although, for ordinary citizens electoral participation is voluntary. The difference is justified on the grounds that Senators are elected by public servants, (mostly elected legislators), rather than by individuals. 'Electing Senators is therefore for these officials a public duty which cannot be shirked'. Birch, 4 citizens, can suffer from bribery and intimidation. 33 By contrast, it is hard to justify a general duty to vote simply because one is a citizen and has a right to vote. No such duty is implied by the case for universal suffrage, which simply supposes that people are equally entitled to vote and to stand as candidates for public office. So the idea that the right not to vote is a trivial right or liberty seems to trivialize the differences in power and responsibility of democratic citizens and legislators and to overlook the legitimate reasons why people might wish to abstain.

The ethics of voting have received little attention from philosophers and political scientists, yet it is plain that they are no more self-evident than other ethical matters.

People can doubt the extent and reliability of their knowledge and judgement, or be unsure of the proper grounds on which to make their decision. They may feel that it would arbitrary and invidious to favour one of the candidates when several or all of them are acceptable and they may, of course, worry about the way that their vote will be interpreted and used by politicians and the media. So, even people who have no conscientious objections to voting might have compelling reasons to prefer abstention to voting in at least some elections, and to do so even if they have the option of voting for 'none of the above'. 33 For a legal case that has influenced my thinking on the importance of distinguishing the rights and duties of leaders and ordinary members, see NAACP v. Alabama, 357. U.S. 449 (1958). The crux of the Supreme Court decision is that ordinary members of the National Association for the Advancement of Colored People, and other organizations, do not have duties of accountability that require them to sacrifice their anonymity. By contrast, leaders of organizations do. The implication is that organizations with no formal leadership will either have to appoint some members who can be held accountable for the behaviour of members, or that all members will have to share in accountability and any loss of privacy that this involves. I look at the implications of equality and responsibility for the case against mandatory public voting in Lever, 2007. Moreover, the case for forcing turnout, but not voting, is obscure. After all, it is low and unequal voting, not turnout, that is the cause of moral and political concern.

While it is likely that many people who have been forced to turn out will then go on to cast legally valid votes, we are here talking psychological probabilities, rather than any conceptual or normative connection between enforced turnout and democratic voting. 34 That is, the reason why people are likely to vote, if they are forced to turn out, is that most people do not like to waste their time. So, if they are forced to queue at polling stations, in order to tick their name off a list, they may well go on to vote, although otherwise they would not have bothered. But from the fact that people do not like to waste their time, and therefore tend to vote, it does not follow that we are justified in forcing them to queue in order to tick their names off an electoral register.

Queuing simply to tick your name off an electoral register seems pretty pointless and annoying. Nor are its pointless and annoying features in any way alleviated because they have been turned into a legal duty. Such a duty, indeed, seems pretty insulting and demeaning, and ill suited to promoting the idea that voting is an important civic duty.

Sharply distinguishing the duty to turnout from the duty to vote might meet some moral objections to compulsory voting the duty to vote. However, the duty to vote, so understood, is no moral duty at all.

Step 5: non-Voting, Free Riding and the Danger of False Analogies As we have seen, the case for compulsory voting turns, importantly, on the thought that non-voters are free-riders, selfishly exploiting the public-spirited efforts of voters. There is, therefore, no moral objection to forcing them to do their share to maintain a democratic system by making voting a legal duty, as well as a right. There are two main problems with this argument. The first is an internal one, of consistency with other aspects of the case for compulsion; the second is the difficulty of showing that legal compulsion is justified even if some voters are free-riders.

The idea that non-voters are selfish exploiters of voters is hard to square with the picture of political inequality that underpins other aspects of the case for compulsory voting. At the start of the case, as we have seen, non-voters are conceptualized as socially deprived in various ways, and as appropriate objects of social democratic concern. Nonvoters, on this picture, find it difficult to protect their own interests-they are, after all, less educated, less experienced and less well-organised than other peopleand so are liable to exploitation by the more powerful, knowledgeable and politically astute. The case for compulsion, indeed, verges on the paternalist, at least as regards this social group, because non-voting is here presented as a threat to their interests, albeit a partially self-induced threat. By contrast, the free-riding justification of compulsion assumes that non-voters are behaving in a self-interested fashion, and seeking to enjoy the benefits of a democratic electoral system without doing their fair share to maintain it.

They seem, therefore, to be exploiting the good will, public spirit and sense of duty of voters, and to be behaving in ways that are selfish and immoral.

These two pictures of non-voters seem to be inconsistent although proponents of compulsion, such as Lijphart, seem not to have noticed the tension between them.

Conversely, while we might want to describe those who voted for Le Pen in France, or the British National Party in the U.K., as selfless contributors to a democratic public good. But this will require considerable argument and cannot be treated as an apriori truth. Nor should we forget that individuals who vote 'tend to have an inflated sense of the potential influence of their votejust as people tend to vastly overestimate their chances of winning lotteries'.(Rose, 317) 35 Hence, there are difficulties with the moral characterization of both voters and non-voters, assumed by free-rider arguments for compulsion.

The second difficulty with the free-riding argument turns on the difficulty of describing the public good which compulsion is supposed to protect. The case for compulsory voting is frequently characterized by analogies between compulsion in the case of voting and compulsion in the case of military service, the education of children, or in the cases of taxation and jury duty. 36 Democratic societies often require people to contribute to some public good and, in the case of compulsory voting, the level of sacrifice or effort required is comparatively small. The argument turns on the assumption that compulsory voting is necessary to protect a public good. But how that good should be characterized is uncertain, given that the extent of turnout one decides upon may have predictable implications for who wins or loses an election, as Lijphart assumes. It might be said that the public good in question is 'legitimacy' or a 'democratic electoral system' or 'a representative political system'. But to make such claims looks like over-kill, and is clearly inconsistent with the idea that there are democratic and legitimate political systems which lack compulsory voting. As these, indeed, seem to be the majority of 'actually existing' democracies, there is clearly something wrong with the idea that democratic legitimacy or representation turns on achieving turnouts in the 90 th percentile, or even in the 80s. The first difficulty with these analogies, therefore, is the idea that compulsory voting is necessary or justified in order to protect a public good even if some voters are free-riders.

But the difficulty with these analogies is more fundamental. Legal requirements to serve on juries, to serve in the army, to pay taxes and to educate our children may help to protect a public good from the temptations posed by free-riding. But it is doubtful that such ideas play a significant role in explaining why such legal duties are justified when they are, as they seem to obscure the very considerable differences in the content, weight and justification of these different duties, as well as to obscure the differences between justified and unjustified forms of each.

For example, the duty to pay taxes applies whether or not one is a citizen, and seems to be characterized by ideas of 'ability to pay', proportionality, and even redistributive justice that are absent from the case for compulsory voting. It is also worth noting that compulsory voting implies that everyone has a legal duty to vote although people will be excused their failure to fulfill that duty if they have conscientious objections to voting. By contrast, the duty to pay income tax below a specified threshold is no legal duty at allalthough the poor, notoriously, have to pay consumption taxes, so that concerns for distributive justice may sometimes justify raising money from taxes on income rather than consumption.

Likewise, the duty to serve on a jury, in systems with jury trials, appeals to moral and political notions of equality, fairness and justice that go well beyond the idea that the state can solve collective action problems via coercion. The duty to serve on a jury importantly reflects the obligation to provide defendants with a jury of their peersthat is, a jury that is made up of people like them, suitably defined. Compulsion is necessary because voluntary participation is likely to lead to juries skewed in all sorts of undesirable ways. So, the main reason why compulsion is justified in the case of jury duty is because we have duties of justice to defendants which constrain what will count as a free and fair trial.

Without belabouring the point, therefore, it looks as though the case for compulsory voting cannot be made to seem innocuous or democratic by comparing it to other duties which we generally accept. The difficulty is that these latter duties have an evident and agreed point to them, whereas whether or not it is desirable to raise and equalize voting, or to use legal compulsion to do so, has still to be established. Moreover, duties to pay taxes, to educate one's children, to serve in the defence of one's country or to serve on juries, are all very different duties, with significantly different justifications. What makes them morally and politically significant and distinct is, inevitably, lost in any attempt to treat them as examples of justified coercion in response to collective action problems. Perhaps we can illuminate these duties by treating them as solutions to the problem of providing and maintaining public goods, given rational selfinterest. But my hunch is that such a perspective is likely to obscure, rather to illuminate, the morally significant features of these different duties and may, indeed, lead to radically undemocratic versions of them.37

C. CONCLUSION

In this paper I have argued that the case for compulsory voting is unproven. It is unproven because the claim that compulsion will have beneficial results rests on speculation about the way that nonvoters will vote if they are forced to vote, and there is considerable, and justified, controversy on this matter. Nor is it clear that compulsory voting is well-suited to combating those forms of low and unequal turnout that are, genuinely, troubling. On the contrary, it may make them worse by distracting politicians and voters from the task of combating persistent, damaging, and pervasive forms of unfreedom and inequality in our societies.

Moreover, I have argued, the idea that compulsory voting violates no significant rights or liberties is mistaken and is at odds with democratic ideas about the proper distribution of power and responsibility in a society. It is also at odds with concern for the politically inexperienced and alienated, which itself motivates the case for compulsion.

Rights to abstain, to withhold assent, to refrain from making a statement, or from participating, may not be very glamorous, but can be nonetheless important for that.

They are necessary to protect people from paternalist and authoritarian government, and from efforts to enlist them in the service of ideals that they do not share. Rights of nonparticipation, no less than rights of anonymous participation, enable the weak, timid and unpopular to protest in ways that feel safe and that are consistent with their sense of duty, as well as self-interest.

True, such forms of protest are can be misinterpreted, and by themselves are unlikely to be wholly successful. But that is true of most forms of protest, and would be true of compulsory voting, itself. 38 After all, it is unclear what meaning we should give to those who queue to tick their names off an electoral register, but then go home without voting. Nor is it evident what we should say about those who voted for "none of the above", other than that they preferred this option to the others that were available. Most protest, and all voting, depends for its success on the behaviour of other people, many of whom we will not know, many of whom will have interests and beliefs quite at odds with our own, and over whose behaviour we have no influence. People must, therefore, have rights to limit their participation in politics and, at the limit, to abstain, not simply because such rights can be crucial to prevent coercion by neighbours, family, employers or the state, but because they are necessary for people to decide what they are entitled to do, what they have a duty to do, and how best to act on their respective duties and rights.

That is not to say that compulsory voting can never be democratic, merely that these are likely to be exceptions, rather than the norm. Legal duties to vote may be necessary to protect the right to vote where the state is weak, and inequalities of power leave peasants at the mercy of landowners, or workers vulnerable to employers. It is also possible that in very large countries, or those riven by ethnic divisions, compulsory voting is necessary to gain support for a system of proportional representation that is fair to all social groups. But these are rather different justifications for compulsion than the ones that we have looked at here, and though they have affinities with arguments that have been made for compulsion in the past, it is unclear what forms of compulsion or of proportionality they would actually justify. For now, the point is simply that the difficulties with the democratic case for compulsion do not mean that compulsory voting cannot serve an important remedial purpose. However, that is rather different from advocating its adoption by long established, stable and seemingly functional democracies.

Bibliography

Ansolabehere. S and Iyengar. S. 1995. Going Negative: How Attack Ads Shrink and Polarize the Electorate. New York. Free Press.

Is Compulsory Voting Justified?

	Public Reason 1.1 (March 2009) 45.62
	Annabelle Lever
	Dept. of Philosophy, London School of Economics

The Netherlands adopted compulsory voting in 1917, along with universal suffrage for men and PR. (women got the vote in 1919). The PR system in use at the time apparently required 100% turnout for the results to be truly proportional. I am curious why this was the system of PR that was adopted, and what connection the adoption of PR had to worries about the consequences of universal suffrage. SeeGratschew, 2004, 29.

Two excellent recent books on voter turnout areWattenberg, 2002[START_REF] Blais | To Vote or Not to vote: the Merits and Limitations of Rational Choice Theory[END_REF]. Gerry Stocker, 2006 emphasises that the problem of declining turnout, while widespread, is particularly acute for established democracies.

Lijphart says that 'low voter turnout means unequal and socioeconomically biased turnout'. (Lijphart, 2) He seems to have been one of the first people to link the two systematically and repeatedly.

I've been told that in Russia, where people can vote for 'none of the above', and are still under various forms of pressure to vote, this is a not-infrequent occurrence at provincial level. A new election is then called. In considering whether or not we should adopt this option, it is necessary to recognise that the result necessarily extends the life of the government who called the election. Consequently, there seems to be a form of 'bias towards the status-quo' in adopting this solution to problems of low turnout.

Kearney and Rogers say 'It will of course be important to prevent the formation of an "Against All" or "None of the Above" party', though how this is to be done, consistent with freedom of political association and expression is not discussed.(Kearney and Rogers, 32, footnote 15).

Alan Wertheimer is a notable exception. See pp. 280-282, and the summary of his argument at p. 290

According to Gratschew, 30 the mere mention of compulsory voting by the Minister for Democracy, in

1999, as a way to increase turnout in Sweden, occasioned heated rejections of it by the media, political scientists and politicians.19 See Ringen 2004. As the TLS cover to his article announced, 'A remarkable study of democracy has reached its conclusion: rule by popular consent is disintegrating before our eyes'. The report referred to is "The Norwegian Study of Power and Democracy", and the English language version can be found at www.sv.uio.no/mutr/english/index.html.

Ballinger is talking about the UK, but there is no reason to suppose that this worry would not apply elsewhere.(Ballinger, 22)

Actually, there is an empirical question about how far the stated 'gains' produced by compulsion refer to turnout rather than voting, and how far they depend on legal requirements to vote rather than to turnout. Ambiguity here makes it important to sort out what, exactly, different figures refer to and what legal background they presuppose.

See, also, Blais, 69, and the suggestion that the tendency to overestimate the significance of one's vote is particularly likely in close elections.

My impression is that most people are just copying Lijphart here. SeeLijphart, 11; Hill, 5; and Kearney and Rogers, 30. However, unlike Hill, Kearney and Rogers do not cite Lijphart as their inspiration.

The theory of rational choice and the theory of moral choice are not the same, just because the requirement of reasoned justification generally attaches to the latter. Depending on background circumstances, it can be rational to exploit or to be exploited; it can be rational to deceive, coerce and blackmail, or to put up with being deceived, coerced and blackmailed. So unless one is careful to build in suitably moral assumptions, there is nothing about an individually or collectively rational decision that requires it to be consistent with democratic norms.

Kearney and Roger seem to think that the ability to vote for 'none of the above' 'would in fact be a far more effective means of withdrawing democratic legitimacy than abstention, as it could not be misread as apathy'. Obviously, this requires people to vote, rather than just to turn up. Apart from that, of course, it is easy to imagine the obvious rejoinder to this, which is that people are being lazy when they voted and it is not going to be at all clear that people ticking this option are not protesting compulsion to vote, rather than the options available.