Pleiotropic Mechanisms Indicated for Sex Differences in Autism

Mitra, Ileena; Tsang, Kathryn; Ladd‐Acosta, Christine; Croen, Lisa; Aldinger, Kimberly A.; Hendren, Robert L.; Traglia, Michela; Lavillaureix, Alinoë; Zaitlen, Noah; Oldham, Michael C.; Levitt, Pat; Nelson, Stanley F.; Amaral, David G.; Herz-Picciotto, Irva; Fallin, M. Daniele

doi:10.1371/journal.pgen.1006425

Cited by 78 publications

(91 citation statements)

References 88 publications

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“…[124]. First, SNPs were filtered using PLINK[63,64] (see web resources) for Hardy-Weinberg equilibrium (HWE), call rate, minor allele frequency (MAF) and Mendel errors separately in each ASD dataset (S6 Table).…”

Section: Methodsmentioning

confidence: 99%

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Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

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Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

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Section: Methodsmentioning

confidence: 99%

“…[124]. For each dataset, the following individual quality control filters were applied using PLINK[63,64]: genotyping rate, heterozygosity rate, verifying individual sex, verifying known relationships, removing individuals contributing to confounding relationship, and keeping one instance of individuals present in multiple studies.…”

Section: Methodsmentioning

confidence: 99%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

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“…Intra-locus sexual conflict is the result of selection acting in divergent directions on male and female phenotypes that are underpinned by a shared genetic architecture 7 . However, both forward 46 and reverse 47,48,83,84 genetic studies have indicated that the genetic architecture underlying many traits expressed in both sexes can differ substantially between females and males. In theory, sex-specific genetic architecture, where an allele affects one sex but not the other, resolves contradictory selection pressures 45,46 and relaxes balancing selection.…”

Section: Clarifying the Role Of Sexual Conflict In Evolutionmentioning

confidence: 99%

Population genetics of sexual conflict in the genomic era

2017

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ABSTRACT:Sexual conflict occurs when selection acts in opposing directions on males and females. Case studies in both vertebrates and invertebrates indicate that sexual conflict maintains genetic diversity through balancing selection, which might explain why many populations show more genetic variation than expected. Recent population genomic approaches based on different measures of balancing selection have suggested that sexual conflict can arise over survival, not just reproductive fitness as previously thought. A fuller understanding of sexual conflict will provide insight into its contribution to adaptive evolution and will reveal the constraints it might impose on populations. In many sexually reproducing species, divergent reproductive interests can arise between the sexes over courtship, fertilization and offspring investment, and these conflicting interests can lead to substantially different optimal phenotypes in males and females [1][2][3] . In such cases, selection will act in opposing directions on the sexes, a situation referred to as sexual conflict or sexual antagonism. Sexual conflict over a given phenotypic trait can occur through the interaction of alleles at two or more loci (inter-locus sexual conflict) [4][5][6] . This form of sexual conflict has been somewhat difficult to study using molecular population genetic methods, as it lacks a clear evolutionary signature in DNA sequence. As a result, the majority of recent population genomic studies have focused on cases where there are genetic trade-offs for male and female fitness from alleles at a single locus (intra-locus sexual conflict). This situation arises when male and female phenotypes are underpinned by the same genetic architecture 7 . With the exception of sex-specific Y and W chromosomes, males and females within a species share the vast majority of their genome, which creates a high potential for intra-locus conflict when male and female reproductive interests are not aligned through strict monogamy. Indeed, classic work measuring reproductive fitness in Drosophila 8 has suggested that intra-locus sexual conflict occurs at many different loci throughout the genome. Intra-locus sexual conflict can be ultimately resolved via alleles or expression patterns that are sex-specific in their effects 9-13 .The persistence of sexual conflict, and the mechanism by which it occurs, have important implications for the nature and magnitude of genetic diversity within populations [14][15][16][17][18][19] .Positive selection and purifying selection deplete populations of genetic variation over time.Nevertheless, many populations display more genetic diversity for traits under strong selection than expected, possibly because of balancing selection generated by intra-locus sexual conflict 15,20 . Intra-locus sexual conflict produces balancing selection by selecting for or against different alleles at a specific locus depending on whether they are present in females or males. The resulting genetic diversity-and by implication sexual conflictshapes t...

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“…Aunque la explicación exacta para este fenómeno no se conoce, se ha visto que las variantes genéticas que regularían rasgos antropométricos y polimorfismos en el cromosoma X darían cuenta de esta diferencia 22 . Por otra parte, aunque no encontramos una clara asociación, existe una tendencia a detectarse un mayor porcentaje de casos con CMA positivo si fueron derivados con CD.…”

Section: Discussionunclassified