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Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the knownFUT2mutant allele conferring resistance to intestinal viruses and anAPOL3variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival.Significance statementHuman genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival.

International audience; Understanding the driving forces and molecular processes underlying dioecy and sex chromosome evolution, leading from hermaphroditism to the occurrence of male and female individuals, is of considerable interest in fundamental and applied research. The genus Phoenix, belonging to the Arecaceae family, consists uniquely of dioecious species. Phylogenetic data suggest that the genus Phoenix has diverged from a hermaphroditic ancestor which is also shared with its closest relatives. We have investigated the cessation of recombination in the sex-determination region within the genus Phoenix as a whole by extending the analysis of P. dactylifera SSR sex-related loci to eight other species within the genus. Phylogenetic analysis of a date palm sex-linked PdMYB1 gene in these species has revealed that sex-linked alleles have not clustered in a species-dependent way but rather in X and Y-allele clusters. Our data show that sex chromosomes evolved from a common autosomal origin before the diversification of the extant dioecious species.

INTRODUCTION : Prenatal counseling for sex chromosome anomalies (SCA) is complex. The observed rate of TOP (termination of pregnancy) varies worldwide and even within countries. The objectives of this vignette study were to quantify agreement between ten prenatal diagnosis centers in Paris and identify reasons for disagreement.METHODS : We submitted online three cases of Turner syndrome, one case of Klinefelter syndrome, one 47, XYY, one mosaicsm 46,XY/45,X and two cases of 47,XXX to one obstetrician, one pediatrician and one geneticist in each of the ten parisian prenatal diagnosis centers. Experts answered online if they would or not accept couples’ demand for TOP. If experts refused, the cases continued and the experts were consulted a second time. We assessed initial and final agreement for acceptance or rejection of TOP. We qualitatively assessed the reasons for acceptance or refusal of TOP.RESULTS : Final agreement to reject TOP was respectively 28%, 74%, 80%, 100% and 74% for Turner syndrome, Klinefelter syndrome, 47,XYY, 47,XXX and mosaicism 46,XY/45,X. These results are quite different from the observed percentage of TOP: respectively 78 and 40% of TOP for Turner and Klinefelter syndrome in the Parisian registry of malformations.Reasons to accept TOP were variable for Turner syndrome, but for other SCA the majority of experts would accept for parental distress. Predominant reason for a refusal of TOP was inadequacy with french law for TOP.CONCLUSION : The results of this declarative survey show decision of TOP for SCA is difficult and subject to many tensions. It enhances the importance of managing these anomalies in specialized prenatal diagnosis centers.; INTRODUCTION : Le conseil prénatal en cas d’anomalie des gonosomes est complexe. Une forte disparité dans le taux d’IMG pour ces anomalies existe dans le monde et entre CPDPN. Cette étude a pour objectif de quantifier la discordance entre 10 CPDPN en Île de France.MÉTHODES : Trois cas de syndrome de Turner, un syndrome de Klinefelter, un 47,XYY, deux cas 47,XXX et une mosaïque 46,XY/45,X ont été soumis sous forme de dossiers progressifs en ligne à un obstétricien, un pédiatre et un (cyto)généticien dans les 10 CPDPN. Ceux-ci devaient formuler leur décision vis-à-vis de la demande d’IMG et son motif. En cas de refus la question leur était à nouveau posée après évolution du cas. Nous avons évalué le pourcentage de concordance pour accepter ou refuser une demande et le motif.RÉSULTATS : À l’issue des cas cliniques, le pourcentage de concordance pour accéder à une demande d’IMG était respectivement de 25%, 1%, 1%, 17% et 1% pour le Turner, Klinefelter, 47,XYY, 47,XXX et la mosaïque. Ces résultats sont très différents du taux d’IMG observées : respectivement 78 et 40% pour syndrome de Turner et Klinefelter selon le registre des malformations de Paris.Pour le syndrome de Turner les motifs pour accéder à une demande d’IMG étaient hétérogènes alors que pour les autres syndromes le choix des experts était en majorité motivé par la détresse du couple. Le motif prédominant de refus était l’inadéquation avec la loi.CONCLUSION : Cette étude témoigne de la difficulté décisionnelle en cas de demande d’IMG pour anomalie des gonosomes et montre que la discussion est soumise à multiples tensions. D’où l’importance de la prise en charge des anomalies des gonosomes au sein des CPDPN.

Besides the established central role of poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 in the maintenance of genomic integrity, accumulating evidence indicates that poly(ADP-ribosyl)ation may modulate epigenetic modifications under physiological conditions. Here, we provide in vivo evidence for the pleiotropic involvement of Parp-2 in both meiotic and postmeiotic processes. We show that Parp-2-deficient mice exhibit severely impaired spermatogenesis, with a defect in prophase of meiosis I characterized by massive apoptosis at pachytene and metaphase I stages. Although Parp-2 −/− spermatocytes exhibit normal telomere dynamics and normal chromosome synapsis, they display defective meiotic sex chromosome inactivation associated with derailed regulation of histone acetylation and methylation and up-regulated X- and Y-linked gene expression. Furthermore, a drastically reduced number of crossover-associated Mlh1 foci are associated with chromosome missegregation at metaphase I. Moreover, Parp-2 −/− spermatids are severely compromised in differentiation and exhibit a marked delay in nuclear elongation. Altogether, our findings indicate that, in addition to its well known role in DNA repair, Parp-2 exerts essential functions during meiosis I and haploid gamete differentiation.

International audience; Segmental duplications on sex chromosomes constitute an important proportion of recent duplications (approximately 30%). Among those, the evolution of duplicated noncoding DNA is still poorly investigated. We focus our work on repeated DNA sequences extensively used in population genetics and evolution: microsatellites. Six duplicated (CA), microsatellite loci, located on the homologous region of human sex chromosomes, were studied at the intraspecific level in Homo sapiens and by an orthologous comparison in eight primate species. At the intraspecific level, we evaluated the congruence in paralogous divergence between the flanking sequences of the six microsatellites and the approximately 2.2-kb surrounding sequences and observed that both phylogenies are congruent. At the interspecific level (8 species of primates: 54 individuals), we analyzed the sequence polymorphism and divergence of each orthologous locus for both the flanking sequence and the microsatellite. The results showed a lower divergence of flanking sequences than expected in noncoding DNA and a relative stability of the first nucleotides close to the microsatellite. The location of each CAIII locus in a Low Copy Repeated element containing duplicated VCX/Y genes (approximately 1 kb) suggested that direct or indirect selection could explain these results. Moreover, the substitution rates in the flanking sequences and in the microsatellites were correlated. Thus, the evolutionary dynamics of microsatellites seems closely linked to the variation of spontaneous mutations in the surrounding regions.

Mammalian sex chromosomes stem from ancestral autosomes and have substantially differentiated. It was shown that X-linked genes have generated duplicate intronless gene copies (retrogenes) on autosomes due to this differentiation. However, the precise driving forces for this out-of-X gene “movement” and its evolutionary onset are not known. Based on expression analyses of male germ-cell populations, we here substantiate and extend the hypothesis that autosomal retrogenes functionally compensate for the silencing of their X-linked housekeeping parental genes during, but also after, male meiotic sex chromosome inactivation (MSCI). Thus, sexually antagonistic forces have not played a major role for the selective fixation of X-derived gene copies in mammals. Our dating analyses reveal that although retrogenes were produced ever since the common mammalian ancestor, selectively driven retrogene export from the X only started later, on the placental mammal (eutherian) and marsupial (metatherian) lineages, respectively. Together, these observations suggest that chromosome-wide MSCI emerged close to the eutherian–marsupial split approximately 180 million years ago. Given that MSCI probably reflects the spread of the recombination barrier between the X and Y, crucial for their differentiation, our data imply that these chromosomes became more widely differentiated only late in the therian ancestor, well after the divergence of the monotreme lineage. Thus, our study also provides strong independent support for the recent notion that our sex chromosomes emerged, not in the common ancestor of all mammals, but rather in the therian ancestor, and therefore are much younger than previously thought., Author Summary Our sex chromosomes have profoundly differentiated since evolving from an ancestral pair of non-sex chromosomes (autosomes). In this study, we first show that X chromosome–derived retrogenes (genes that arose as duplicates of “parental” X-linked genes) are specifically expressed during the meiotic and postmeiotic stages of spermatogenesis, thus functionally replacing their parents during, but also after, the process of male meiotic sex chromosome inactivation (MSCI). We then show that the “export” of retroposed gene copies from the X chromosome started rather recently during mammalian evolution, on the eutherian (“placental” mammal) and marsupial lineages, respectively. This suggests that MSCI—the main driving force for this out of the X gene “movement”—originated around the separation of these two major (therian) mammalian lineages, approximately 180 million years ago. Given that MSCI was likely triggered as soon as the proto-X and -Y chromosomes ceased to recombine (an event that marks the origin of these sex chromosomes), our data also support the recent notion that our sex chromosomes and those of other therians emerged, not in the common ancestor of all mammals, but—probably rather late—in the therian ancestor., By dating the evolutionary onset of gene export from the X chromosome, researchers reveal the age of meiotic sex chromosome inactivation in mammals and suggest a rather recent origin of our sex chromosomes.

Background Considerable progress has been made in our understanding of sex determination and dosage compensation mechanisms in model organisms such as C. elegans, Drosophila and M. musculus. Strikingly, the mechanism involved in sex determination and dosage compensation are very different among these three model organisms. Birds present yet another situation where the heterogametic sex is the female. Sex determination is still poorly understood in birds and few key determinants have so far been identified. In contrast to most other species, dosage compensation of bird sex chromosomal genes appears rather ineffective. Results By comparing microarrays from microdissected primitive streak from single chicken embryos, we identified a large number of genes differentially expressed between male and female embryos at a very early stage (Hamburger and Hamilton stage 4), long before any sexual differentiation occurs. Most of these genes are located on the Z chromosome, which indicates that dosage compensation is ineffective in early chicken embryos. Gene ontology analyses, using an enhanced annotation tool for Affymetrix probesets of the chicken genome developed in our laboratory (called Manteia), show that among these male-biased genes found on the Z chromosome, more than 20 genes play a role in sex differentiation. Conclusions These results corroborate previous studies demonstrating the rather inefficient dosage compensation for Z chromosome in birds and show that this sexual dimorphism in gene regulation is observed long before the onset of sexual differentiation. These data also suggest a potential role of non-compensated Z-linked genes in somatic sex differentiation in birds.