Pierre Fontanillas

Nonshivering thermogenesis capacity associated to mitochondrial DNA haplotypes and gender in the greater white-toothed shrew, Crocidura russula.

A selection gradient was recently suggested as one possible cause for a clinal distribution of mitochondrial DNA (mtDNA) haplotypes along an altitudinal transect in the greater white‐toothed shrew, Crocidura russula (Ehinger et al. 2002). One mtDNA haplotype (H1) rare in lowland, became widespread when approaching the altitudinal margin of the distribution. As H1 differs from the main lowland haplotype by several nonsynonymous mutations (including on ATP6), and as mitochondria play a crucial role in metabolism and thermogenesis, distribution patterns might stem from differences in the thermogenic capacity of different mtDNA haplotypes.

Dominance and the evolutionary accumulation of cis- and trans-effects on gene expression

Gene expression levels appear to be under pervasive stabilizing selection. Yet the genetic architecture underlying abundant gene expression diversity within and between populations remains elusive. Here, we investigated the role of dominance in the segregation of cis- and trans-regulation within and between populations. We used chromosome substitution lines of Drosophila melanogaster to show that (i) >70% of the genes that are differentially expressed between two homozygous lines are masked in the heterozygous, suggesting that one of the substituted chromosomes contains a recessive allele; (ii) such large masking is already obtained with heterozygous chromosomes originating from the same population, with the time of divergence between chromosomes in heterozygous lines making only a small but significant contribution to the masking of variation observed in homozygous lines; (iii) variation in gene expression due to trans-regulation is biased toward greater deviations from additivity because of recessive and dominant alleles, whereas variation due to cis-regulation shows higher additivity; and (iv) genetic divergence between second chromosomes is associated with increased cis-regulation, whereas the level of trans-regulation shows little increase over the time scale studied. Our results indicate that cis-acting alleles may be preferentially fixed by positive natural selection because of their higher additivity, and that the disruption of gene expression by recessive variation with pervasive trans-effects may be important for understanding gene expression variation within populations. We suggest that widespread regulatory effects of recessive low-frequency homozygous variation may provide a general mechanism mediating disease phenotypes and the genetic load of natural populations.

Inbreeding in the greater white-toothed shrew, Crocidura russula

Abstract We combined mark‐and‐recapture studies with genetic techniques of parentage assignment to evaluate the interactions between mating, dispersal, and inbreeding, in a free‐ranging population of Crocidura russula. We found a pattern of limited and female‐biased dispersal, followed by random mating within individual neighborhoods. This results in significant inbreeding at the population level: mating among relatives occurs more often than random, and FIT analyses reveal significant deficits in heterozygotes. However, related mating partners were not less fecund, and inbred offspring had no lower lifetime reproductive output. Power analyses show these negative results to be quite robust. Absence of phenotypic evidence of inbreeding depression might result from a history of purging: local populations are small and undergo disequilibrium gene dynamics. Dispersal is likely caused by local saturation and (re)colonization of empty breeding sites, rather than inbreeding avoidance.

Key considerations for measuring allelic expression on a genomic scale using high-throughput sequencing

Differences in gene expression are thought to be an important source of phenotypic diversity, so dissecting the genetic components of natural variation in gene expression is important for understanding the evolutionary mechanisms that lead to adaptation. Gene expression is a complex trait that, in diploid organisms, results from transcription of both maternal and paternal alleles. Directly measuring allelic expression rather than total gene expression offers greater insight into regulatory variation. The recent emergence of high‐throughput sequencing offers an unprecedented opportunity to study allelic transcription at a genomic scale for virtually any species. By sequencing transcript pools derived from heterozygous individuals, estimates of allelic expression can be directly obtained. The statistical power of this approach is influenced by the number of transcripts sequenced and the ability to unambiguously assign individual sequence fragments to specific alleles on the basis of transcribed nucleotide polymorphisms. Here, using mathematical modelling and computer simulations, we determine the minimum sequencing depth required to accurately measure relative allelic expression and detect allelic imbalance via high‐throughput sequencing under a variety of conditions. We conclude that, within a species, a minimum of 500–1000 sequencing reads per gene are needed to test for allelic imbalance, and consequently, at least five to 10 millions reads are required for studying a genome expressing 10 000 genes. Finally, using 454 sequencing, we illustrate an application of allelic expression by testing for cis‐regulatory divergence between closely related Drosophila species.

ESTIMATING SEX‐SPECIFIC DISPERSAL RATES WITH AUTOSOMAL MARKERS IN HIERARCHICALLY STRUCTURED POPULATIONS

Abstract –A recent study suggests that sex‐specific dispersal rates can be quantitatively estimated on the basis of sex‐ and state‐specific (pre‐ vs. postdispersal) F‐statistics. In the present paper, we extend this approach to account for the hierarchical structure of natural populations, and we validate it through individual‐based simulations. The model is applied to an empirical data set consisting of 536 individuals (males, females, and predispersal juveniles) of greater white‐toothed shrews (Crocidura russula), sampled according to a hierarchical design and typed for seven autosomal microsatellite loci. From this dataset, dispersal is significantly female biased at the local scale (breeding‐group level), but not at the larger scale (among local populations). We argue that selective pressures on dispersal are likely to depend on the spatial scale considered, and that short‐distance dispersal should mainly respond to kin interactions (inbreeding or kin competition avoidance), which exert differential pressure on males and females.

Rapid genotypic change and plasticity in arbuscular mycorrhizal fungi is caused by a host shift and enhanced by segregation.

Arbuscular mycorrhizal fungi (AMF) are among the most abundant symbionts of plants, improving plant productivity and diversity. They are thought to mostly grow vegetatively, a trait assumed to limit adaptability. However, AMF can also harbor genetically different nuclei (nucleotypes). It has been shown that one AMF can produce genotypically novel offspring with proportions of different nucleotypes. We hypothesized that (1) AMF respond rapidly to a change of environment (plant host) through changes in the frequency of nucleotypes; (2) genotypically novel offspring exhibit different genetic responses to environmental change than the parent; and (3) genotypically novel offspring exhibit a wide range of phenotypic plasticity to a change of environment. We subjected AMF parents and offspring to a host shift. We observed rapid and large genotypic changes in all AMF lines that were not random. Genotypic and phenotypic responses were different among offspring and their parents. Even though growing vegetatively, AMF offspring display a broad range of genotypic and phenotypic changes in response to host shift. We conclude that AMF have the ability to rapidly produce variable progeny, increasing their probability to produce offspring with different fitness than their parents and, consequently, their potential adaptability to new environmental conditions. Such genotypic and phenotypic flexibility could be a fast alternative to sexual reproduction and is likely to be a key to the ecological success of AMF.

Mitochondrial DNA variation along an altitudinal gradient in the greater white‐toothed shrew, Crocidura russula

The distribution of mitochondrial control region‐sequence polymorphism was investigated in 15 populations of Crocidura russula along an altitudinal gradient in western Switzerland. High‐altitude populations are smaller, sparser and appear to undergo frequent bottlenecks. Accordingly, they showed a loss of rare haplotypes, but unexpectedly, were less differentiated than lowland populations. Furthermore, the major haplotypes segregated significantly with altitude. The results were inconsistent with a simple model of drift and dispersal. They suggested instead a role for historical patterns of colonization, or, alternatively, present‐day selective forces acting on one of the mitochondrial genes involved in metabolic pathways.

Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk

Background—Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results—To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75×10−7 for IMTmax; replication P=7.24×10−6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P=6.53×10−6, n=13 591; and 0.95 [0.92–0.98], P=1.83×10−4, n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions—This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Replication and characterization of CADM2 and MSRA genes on human behavior

Progress identifying the genetic determinants of personality has historically been slow, with candidate gene studies and small-scale genome-wide association studies yielding few reproducible results. In the UK Biobank study, genetic variants in CADM2 and MSRA were recently shown to influence risk taking behavior and irritability respectively, representing some of the first genomic loci to be associated with aspects of personality. We extend this observation by performing a personality “phenome-scan” across 16 traits in up to 140,487 participants from 23andMe for these two genes. Genome-wide heritability estimates for these traits ranged from 5–19%, with both CADM2 and MSRA demonstrating significant effects on multiple personality types. These associations covered all aspects of the big five personality domains, including specific facet traits such as compliance, altruism, anxiety and activity/energy. This study both confirms and extends the original observations, highlighting the role of genetics in aspects of mental health and behavior.

Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2–4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.