Infertility is a major health concern affecting 15% of couples of reproductive-age worldwide (Mascarenhas et al., 2012; Boivin et al., 2007). The infertility burden has increased globally for both genders in the past 30 years (Sun et al., 2019), and now affects approximately 50 million couples worldwide (Datta et al., 2016). Infertility is broadly treated by assisted reproductive technologies (ART), and today the number of individuals who were conceived by ART is close to 0.1% of the total world population, with over 8 million children already born following in vitro fertilization (IVF). Currently, ART is estimated to account for 1–6% of births in most countries (Faddy et al., 2018), with over 2.5 million cycles performed every year, resulting in over 500,000 births worldwide annually (Fauser, 2019). Despite this undeniable success, almost half the couples who seeks medical assistance for infertility fail to achieve successful pregnancy, and nearly 40% of infertile couples worldwide are simply diagnosed with unexplained or idiopathic infertility (Sadeghi, 2015). In the clinical context, few efforts are currently being made to understand and specifically address the underlying causes of a couple’s infertility because ART can often successfully rescue fertility even without a molecular diagnosis. Nevertheless, this absence of identification of the causes of infertility means that we lack alternative treatments for couples for whom current therapies are unsuccessful. Consequently, it is essential to improve the molecular diagnosis of infertility.

Human male infertility is a clinically heterogeneous condition with a complex etiology, in which genetic defects play a significant role. It is estimated that half of idiopathic cases of male infertility could be attributed to an as-yet unidentified genetic defect (Krausz, 2011). However, characterization of the molecular causes of male infertility represents a significant challenge, as over 4000 genes are thought to be involved in sperm production (Jan et al., 2017). Over the past decade, significant progress has been made in gene identification thanks to the emergence of next-generation sequencing (NGS), and in functional gene validation thanks to new gene-editing techniques such as CRISPR/Cas9. NGS provides an inexpensive and rapid genetic approach through which to discover novel disease-associated genes (Fernandez-Marmiesse et al., 2018). It has proven to be a highly powerful tool in the research and diagnosis context of male infertility (Xavier et al., 2021; Krausz and Riera-Escamilla, 2018). In addition, validation of newly-identified variants through functional experiments has greatly benefited from the ability to generate mouse knock-out models using CRISPR technology (Kherraf et al., 2018) and the use of novel model organisms like Trypanosoma brucei to study specific phenotypes, such as multiple morphological abnormalities of the [sperm] flagella (MMAF) syndrome (Coutton et al., 2018; Lorès et al., 2019; Martinez et al., 2020). These developments have resulted in a diagnostic yield, based on known genetic causes, explaining about 50% of cases of rare qualitative sperm defects like globozoospermia, acephalic, or MMAF syndromes (Beurois et al., 2020; Touré et al., 2021). In contrast, the diagnostic yield for quantitative sperm abnormalities such as oligozoospermia or azoospermia remains below 20%, even though these are the most common forms of male infertility (Krausz, 2011; Krausz and Riera-Escamilla, 2018; Tüttelmann et al., 2018). To improve these low diagnostic yields, international consortia have been created to attempt to identify very low-frequency variants (https://gemini.conradlab.org/ and https://www.imigc.org/). In addition, several groups have started to assemble cohorts of patient-parent trios, aiming to identify de novo mutations causing male infertility as well as providing insight into dominant maternal inheritance (Xavier et al., 2021; Veltman and Brunner, 2012; McRae, 2017). Phenotypic heterogeneity and apparent incomplete penetrance were observed for some genetic alterations involved in male infertility (Vogt, 2005; Röpke et al., 2013; Kherraf et al., 2017). These observations are difficult to reconcile with a model of Mendelian inheritance. We thus raised the possibility that the low diagnostic yield is partly due to the complex etiology of infertility, and hypothesized that some of the unsolved cases are due to oligogenic events, that is, accumulation of several rare hypomorphic variants in distinct, functionally connected genes, and in particular to oligogenic heterozygosity. The molecular basis of oligogenicity is poorly understood. The main hypotheses are that two or more mutant proteins may act at different levels in the same intracellular pathway and could quantitatively contribute to its progressive dysfunction. When a critical threshold is reached, the disease phenotype would emerge. Alternatively, the mutant nonfunctional proteins produced may be part of the same multiprotein complex, and the presence of numerous pathogenic variants would increase the chance of the complex becoming compromised – leading to a progressive collapse of its cellular function (Kousi and Katsanis, 2015).

Here, we addressed the oligogenic heterozygosity hypothesis in male infertility using four specially-generated MMAF knock-out (KO) mouse models with autosomal recessive inheritance (Coutton et al., 2018; Coutton et al., 2019). Following extensive cross-breeding of our KO mouse lines, we produced lines harboring between one and four heterozygous truncating mutations. We assessed and compared fertility for these lines, analyzing both quantitative and qualitative sperm parameters, and performed a fine analysis of sperm nuclear morphology for all strains. Using this strategy, we were able to describe new genetic inheritance of sperm deficiencies.

The aim of this study was to determine whether the accumulation of several rare heterozygous variants in functionally connected genes affected fertility and sperm parameters in mice. Our results clearly demonstrated that spermatogenesis failure can arise from oligogenic heterozygosity in mice. Males bearing increased numbers of heterozygote mutations in genes involved in MMAF syndrome exhibited altered spermatocytogram, with significant increase of proportion of abnormal sperm and decreased sperm motility. Both defective sperm motility and abnormal sperm head morphology could negatively impact fertility. Concerning sperm motility, it has been clearly shown that the percentage of conception depends on the total number of motile sperm within the semen (Publicover and Barratt, 2011). Sperm motility is indeed a key parameter for fertilization, which occurs deeply in the mammalian female tract. Motility is necessary not only for the sperm to reach the oocyte in the oviduct, but sperm motility is also required for the sperm to cross the protective layers of the oocytes and is essential for gamete fusion (Ravaux et al., 2016). Concerning abnormal head morphology, there are numerous reports of a significant correlation between morphology and infertility and it is accepted that any increase in any sperm abnormality should be regarded as a possible cause of decreased fertility, and that precise analyses of sperm abnormalities is a useful approach for diagnosis or research purposes (Andrade-Rocha, 2001; Chemes and Rawe, 2003; Menkveld et al., 2011; Auger et al., 2016). These findings are supported by the World Health Organization which concludes in its report that ‘categorizing all abnormal forms of spermatozoa may be of diagnostic or research benefit’.

However, despite significant sperm parameter alterations, we did not observe here effect on male fertility, suggesting that the threshold leading to the partial/complete collapse of the male reproductive function was not reached. This concept of threshold is strongly associated with oligogenicity. It is defined by the number of mutations within the same multiprotein complex or intracellular pathway beyond which a disease phenotype will be observed (Dipple and McCabe, 2000). In this study, we induced mutations in four genes coding for proteins participating in flagella formation and function. Although we did observe a negative cumulative burden, we did not reach the complex or system threshold that would lead to the emergence of a dichotomous severe infertility phenotype. This may be related to the fact that the mouse model has proved limitations to decipher the function of the proteins involved in sperm physiology and to assess the impact of their lack on fertilization. These limitations are the housing conditions, the mating protocol and the very high fertility of this model. For instance, concerning the housing conditions, the function of MAGE cancer testis antigens to protect the male germline is revealed only when males are subjected to an environmental stress (Fon Tacer et al., 2019). For mating protocol, the phenotyping is performed in particular conditions where mutated males are mated with wild-type females, without competition and in breeding conditions masking complex phenotypes. An example of such a limitation of classical reproductive phenotyping has been emphasized in the study on the importance of the Pkdrej protein in sperm capacitation (Sutton et al., 2008). Another remarkable exemple is the phenotype of Enkurin KO mice, with variable impact on litter size, despite the function of the protein in flagellum beating (Jungnickel et al., 2018). Overall, the highly significant increase of sperm defects (decrease of sperm motility and increase of head morphological defects) induced by the accumulation of deficient proteins shown in this study would probably impact male fertility in more challenging conditions in mouse. Moreover, the mouse model has much higher fertility than human. Human spermatogenesis is clearly less efficient than that of mice and the level of male infertility is around 15% whereas is less than 1% in mice. It is therefore to be expected that the various defects we noticed in this study will impact more severely human sperm fertilizing competence.

A similar mutational burden in humans, known to have the highest number of sperm defect among primates (Martinez and Garcia, 2020), could, however, be sufficient to reach the threshold for fertility collapse. It is worth noting that the probability of accumulating this type of heterozygous mutations in testis is considerable, because (i) thousands of genes are necessary to achieve spermatogenesis (Jan et al., 2017), (ii) expression of most spermatogenesis-associated genes is restricted to or strongly enriched in the testis (Uhlén et al., 2016), and consequently (iii) the risk of life-threatening impact of mutations is limited.

Moreover, mutant gene products retaining some residual function could be influenced by additional systemic perturbation (see review in Vander Borght and Wyns, 2018) that would lead to system collapse. For instance, environmental factors commonly responsible for milder alterations to spermatogenesis could play an important role by severely aggravating the genetic burden on the system. This type of multi-factorial input could explain the phenotypic continuum observed in patients with idiopathic infertility.

In this article, we showed that the haplo-insufficiency of several genes involved in flagellum biogenesis and associated with MMAF syndrome leads to head defects. When one thinks of MMAF patients, one immediately visualizes flagellar defects. However, the phenotype is more complex and head defects have been associated with the flagellar phenotype since the first publications (Coutton et al., 2018; Dong et al., 2018). This is particularly the case for CFAP43/44 described in this report showing that the complete lack of these genes in KO males also strongly alters head patterning (Coutton et al., 2018). These head defects can actually be explained by the molecular function of the genes studied: CFAP43 is involved in intra-manchette transport (Yu et al., 2021) and it has been previously shown through the study of several genes such as Azh (Mendoza-Lujambio et al., 2002), Clip170 (Akhmanova et al., 2005), Rim-bp3 (Zhou et al., 2009), or Azil (Hall et al., 2013), that manchette modifications impact the head shape of the sperm. The implication of ARMC2 in intraflagellar transport has also recently been shown (Lechtreck et al., 2022) and several previous reports associated sperm head malformations with IFT genes, like IFT20 (Zhang et al., 2016), IFT25 (Liu et al., 2017), IFT27 (Zhang et al., 2017), or IFT88 (San Agustin et al., 2015). Finally, CCDC146 was described as a centriolar proteins (Firat-Karalar et al., 2014) and other centriolar proteins are known to induce sperm head defects (Hwang et al., 2021). If the significant increase in head defects can be easily explained, we do not know why flagellar defects increase simultaneously very little.

As descriptions of animal reproductive phenotypes are becoming increasingly sophisticated and standardized (Houston et al., 2021), emerging tools such as the software used in this study to analyze nuclear morphology should be used to extensively study reproductive phenotypes, including studies of MMAF syndromes, to accurately document head defects.

For the first time, we were able to objectively document defects linked to MMAF using NMAS. This original method allows objective comparison of the impact of mutations on sperm head morphology. We found for Cfap43^-/- and Cfap44^-/- mice that sperm heads predominantly displayed a ‘pepper’ shape – characterized by a broadening of the base (median widths of body were 3.44 ± 0.09 µm and 3.93 ± 0.09 µm for Cfap43^-/- and Cfap44^-/- respectively, versus 2.95 ± 0.06 µm and 3.09 ± 0.12 µm for Armc2^-/- and ccdc146^-/- mice, respectively) and that the flagellum insertion notch had a reduced size. Armc2^-/- sperm show moderate enlargement extending along the entire length of the head, including the hook (length of hook increase from 7.55 ± 0.03 µm to 8.23 ± 0.05 µm between Armc2^+/+ and Armc2^-/- mice), and an increase in circularity (increase from 0.55 to 0.61 between Armc2^+/+ and Armc2^-/- mice) resulting in a more rounded appearance. Ccdc146^-/- sperm presented a total disorganization of the base with complete erasure of the flagellum insertion notch, and an overall decrease in size (mean area decrease from 111.86 ± 0.41 µm² to 96.78 ± 1.08 µm² between ccdc146^+/+ and ccdc146^-/- mice), resulting in heads with a triangular aspect characteristic of the ‘claw’ shape. It is worth to note that the effect on sperm head shape was gene-dependent, with a milder effect observed for Armc2 and a stronger effect observed for Cfap43, Cfap44, and Ccd146. This result was notable as the flagellum phenotype of Armc2 is as severe as that observed with mutation of the other genes. Consequently, sperm head defects are not due to failed flagellum biogenesis. Thus, compared to the other proteins, Armc2 may be less involved in functions other than flagellum biogenesis. It should be noted that NMAS analysis is complementary to the human visual analysis made from optical microscopy and does not replace it because the nature of the detected defects is slightly different. Indeed, the software can detect fine nuclear shape anomalies that are undetectable to the human eye and thus reveals morphological variations that are not retained visually by the experimenter. In this study, NMAS revealed a head morphology variation of Armc2^+/- versus Armc2^+/+ sperm (Figure 3B) that had not been detected by visual analysis (Figure 3A). On the other hand, NMAS does not identify some abnormalities evidenced by light microscopy stains such as acrosome or flagellum insertion defects. For instance, this was illustrated by the similarity of the nuclear profiles observed between Cfap43^+/-, Cfap44^+/- and their wild-type counterparts (+/-), while abnormalities were clearly detected by light microscopy (Figures 1A and 2A). To summarize, we believe that NMAS will bring as much to the study of morphological defects of the head as CASA has brought to the study of defects of sperm motility.

Among the proteins encoded by previously identified MMAF genes, some belong to complexes involved in intraflagellar transport (Liu et al., 2019a; Liu et al., 2019b; Chung et al., 2014), protein degradation (Shen et al., 2019) or unknown processes (Coutton et al., 2019; Lorès et al., 2018) that could affect head formation, and subsequently sperm DNA. As there is a strong relationship between cytoskeletal and chromosomal effects, the question of the potential impact of the accumulation of mutations on sperm chromatin organization arises. Another interesting question would be to investigate whether the damaged heads correspond to those carrying the mutated alleles. Future studies will be eagerly awaited to elucidate the molecular basis of oligogenicity in male infertility. Therefore, we recommend that head morphology should not be overlooked when studying MMAF syndromes, despite an obvious focus on flagellum anomalies.Despite a strong focus on sperm head defects, we also showed that sperm motility was altered in the presence of ≥2 heterozygote mutations. Thus, the function of the flagellum is affected, and an absence of morphological defects should therefore not be considered synonymous with absence of functional defects. More importantly, these results support the hypothesis that idiopathic human asthenozoospermia may be due to an accumulation of heterozygous mutations in genes known to be involved in flagellum biogenesis.

To date, the inheritance pattern of isolated male infertility was only known to be Mendelian – that is, based on a single locus – and the possibility of oligogenic inheritance had not been explored. In contrast, an oligogenic etiology for female infertility has been proposed to be associated with primary ovarian insufficiency (POI) by several groups, in particular due to the identification of heterozygous mutations in several genes associated with POI (Patiño et al., 2017). Oligogenic inheritance has also previously been suggested in another reproductive disorder: congenital hypogonadotropic hypogonadism (Pitteloud et al., 2007), as well as in several non-reproductive disorders (Li et al., 2017). Our results demonstrate that oligogenic inheritance may be linked to both male and female human infertility, and should therefore also be accurately measured when investigating male infertility.

In conclusion, in this article, we report the first evidence of oligogenic inheritance in altered spermatogenesis, leading to teratoasthenozoospermia. This mode of inheritance is crucial as oligogenic events could be behind the difficulties encountered by a significant proportion of infertile couples, for whom the current diagnosis is the somewhat unsatisfactory ‘unexplained’ or ‘idiopathic’ infertility. Our study was conducted in a context of teratozoospermia, a qualitative disorder of spermatogenesis. It paves the way for further studies on other male infertility disorders, including quantitative disorders, such as oligozoospermia or azoospermia for which the diagnostic yield remains very low. Current genetic tests to explore male infertility focus primarily on identifying low-frequency fully-penetrant monogenic defects, which are usually autosomal recessive and linked to the most severe cases of male infertility. However, investigation of oligogenic inheritance in the huge cohorts available should provide an estimate of the frequency of such events. These investigations could potentially identify new candidate genes involved in male infertility.

The discovery presented here is of major medical interest, and has implications for both clinical genetics and infertility management. First, the continuous and exponential characterization of new genes involved in infertility over the last decade offers the hope that, in the near future, an almost exhaustive list of genes and mutations involved in human infertility will be available. The identification of and screening for all known mutant alleles linked to male infertility at the heterozygous level should improve the diagnostic yield. Second, the discovery of multiple mutated genes will allow clinicians to provide more accurate genetic counselling to patients, and better guide them in their infertility journey. To improve patient management, future studies should look at potential correlations between patients’ mutational burden and their intracytoplasmic sperm injection (ICSI) success, pregnancies achieved, and live birth rates. It will also be essential to assess the impact of mutational load on parameters known to influence these outcomes.

Figure 5 - Source Data 1, Figure 6 - Source Data 1 and Figure 7 - Source Data 1 contain the numerical data used to generate the figures.

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Author details

1. Guillaume Martinez

   1. Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France
   2. UM de Génétique Chromosomique, Hôpital Couple-Enfant, CHU Grenoble Alpes, Grenoble, France

   Contribution

   Investigation, Conceptualization, Funding acquisition, Methodology, Supervision, Writing - original draft, Writing - review and editing

   For correspondence

   gmartinez@chu-grenoble.fr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7572-9096

2. Charles Coutton

   1. Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France
   2. UM de Génétique Chromosomique, Hôpital Couple-Enfant, CHU Grenoble Alpes, Grenoble, France

   Contribution

   Investigation, Conceptualization, Formal analysis, Funding acquisition, Methodology, Resources, Supervision, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

3. Corinne Loeuillet

   Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

4. Caroline Cazin

   1. Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France
   2. UM GI-DPI, CHU Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

5. Jana Muroňová

   Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

6. Magalie Boguenet

   Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

7. Emeline Lambert

   Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

8. Magali Dhellemmes

   Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

9. Geneviève Chevalier

   Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

10. Jean-Pascal Hograindleur

    Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

    Contribution

    Funding acquisition

    Competing interests

    No competing interests declared

11. Charline Vilpreux

    Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

    Contribution

    Funding acquisition

    Competing interests

    No competing interests declared

12. Yasmine Neirijnck

    Department of Genetic Medicine and Development, University of Geneva Medical School, Genève, Switzerland

    Contribution

    Funding acquisition

    Competing interests

    No competing interests declared

13. Zine-Eddine Kherraf

    1. Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France
    2. UM GI-DPI, CHU Grenoble Alpes, Grenoble, France

    Contribution

    Funding acquisition

    Competing interests

    No competing interests declared

14. Jessica Escoffier

    Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France

    Contribution

    Funding acquisition

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-8166-5845

15. Serge Nef

    Department of Genetic Medicine and Development, University of Geneva Medical School, Genève, Switzerland

    Contribution

    Funding acquisition, Resources

    Competing interests

    No competing interests declared

16. Pierre F Ray

    1. Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France
    2. UM GI-DPI, CHU Grenoble Alpes, Grenoble, France

    Contribution

    Investigation, Formal analysis, Methodology, Resources, Writing - original draft

    Competing interests

    No competing interests declared

17. Christophe Arnoult

    1. Institute for Advanced Biosciences, INSERM, CNRS, Université Grenoble Alpes, Grenoble, France
    2. Station de Primatologie, UPS 846, CNRS, Rousset, France

    Contribution

    Investigation, Conceptualization, Formal analysis, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review and editing

    For correspondence

    christophe.arnoult@univ-grenoble-alpes.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3753-5901

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