Evolutionary Analysis of Classical HLA Class I and II Genes Suggests That Recent Positive Selection Acted on DPB1*04∶01 in Japanese Population

The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04∶01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04∶01. The DPB1*04∶01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06∶04 and DPB1*04∶01 observed in Japanese cannot be explained without positive selection favoring DPB1*04∶01. The selection coefficient of DPB1*04∶01 was estimated as 0.041 (95% credible interval 0.021–0.077). Our results suggest that DPB1*04∶01 has recently undergone strong positive selection in Japanese population.     

Allelic Variant in the Anti-Müllerian Hormone Gene Leads to Autosomal and Temperature-Dependent Sex Reversal in a Selected Nile Tilapia Line

Owing to the demand for sustainable sex-control protocols in aquaculture, research in tilapia sex determination is gaining momentum. The mutual influence of environmental and genetic factors hampers disentangling the complex sex determination mechanism in Nile tilapia (Oreochromis niloticus). Previous linkage analyses have demonstrated quantitative trait loci for the phenotypic sex on linkage groups 1, 3, and 23. Quantitative trait loci for temperature-dependent sex reversal similarly reside on linkage group 23. The anti-Müllerian hormone gene (amh), located in this genomic region, is important for sexual fate in higher vertebrates, and shows sexually dimorphic expression in Nile tilapia. Therefore this study aimed at detecting allelic variants and marker-sex associations in the amh gene. Sequencing identified six allelic variants. A significant effect on the phenotypic sex for SNP ss831884014 (p<0.0017) was found by stepwise logistic regression. The remaining variants were not significantly associated. Functional annotation of SNP ss831884014 revealed a non-synonymous amino acid substitution in the amh protein. Consequently, a fluorescence resonance energy transfer (FRET) based genotyping assay was developed and validated with a representative sample of fish. A logistic linear model confirmed a highly significant effect of the treatment and genotype on the phenotypic sex, but not for the interaction term (treatment: p<0.0001; genotype: p<0.0025). An additive genetic model proved a linear allele substitution effect of 12% in individuals from controls and groups treated at high temperature, respectively. Moreover, the effect of the genotype on the male proportion was significantly higher in groups treated at high temperature, giving 31% more males on average of the three genotypes. In addition, the groups treated at high temperature showed a positive dominance deviation (+11.4% males). In summary, marker-assisted selection for amh variant ss831884014 seems to be highly beneficial to increase the male proportion in Nile tilapia, especially when applying temperature-induced sex reversal.     

ARLTS1 and Prostate Cancer Risk - Analysis of Expression and Regulation

Prostate cancer (PCa) is a heterogeneous trait for which several susceptibility loci have been implicated by genome-wide linkage and association studies. The genomic region 13q14 is frequently deleted in tumour tissues of both sporadic and familial PCa patients and is consequently recognised as a possible locus of tumour suppressor gene(s). Deletions of this region have been found in many other cancers. Recently, we showed that homozygous carriers for the T442C variant of the ARLTS1 gene (ADP-ribosylation factor-like tumour suppressor protein 1 or ARL11, located at 13q14) are associated with an increased risk for both unselected and familial PCa. Furthermore, the variant T442C was observed in greater frequency among malignant tissue samples, PCa cell lines and xenografts, supporting its role in PCa tumourigenesis. In this study, 84 PCa cases and 15 controls were analysed for ARLTS1 expression status in blood-derived RNA. A statistically significant (p = 0.0037) decrease of ARLTS1 expression in PCa cases was detected. Regulation of ARLTS1 expression was analysed with eQTL (expression quantitative trait loci) methods. Altogether fourteen significant cis-eQTLs affecting the ARLTS1 expression level were found. In addition, epistatic interactions of ARLTS1 genomic variants with genes involved in immune system processes were predicted with the MDR program. In conclusion, this study further supports the role of ARLTS1 as a tumour suppressor gene and reveals that the expression is regulated through variants localised in regulatory regions.     

Interspecific crossing and genetic mapping reveal intrinsic genomic incompatibility between two Senecio species that form a hybrid zone on Mount Etna,Sicily

Studies of hybridizing species can reveal much about the genetic basis and maintenance of species divergence in the face of gene flow. Here we report a genetic segregation and linkage analysis conducted on F₂ progeny of a reciprocal cross between Senecio aethnensis and S. chrysanthemifolius that form a hybrid zone on Mount Etna, Sicily, aimed at determining the genetic basis of intrinsic hybrid barriers between them. Significant transmission ratio distortion (TRD) was detected at 34 (∼27%) of 127 marker loci located in nine distinct clusters across seven of the ten linkage groups detected, indicating genomic incompatibility between the species. TRD at these loci could not be attributed entirely to post-zygotic selective loss of F₂ individuals that failed to germinate or flower (16.7%). At four loci tests indicated that pre-zygotic events, such as meiotic drive in F₁ parents or gametophytic selection, contributed to TRD. Additional tests revealed that cytonuclear incompatibility contributed to TRD at five loci, Bateson–Dobzhansky–Muller (BDM) incompatibilities involving epistatic interactions between loci contributed to TRD at four loci, and underdominance (heterozygote disadvantage) was a possible cause of TRD at one locus. Major chromosomal rearrangements were probably not a cause of interspecific incompatibility at the scale that could be examined with current map marker density. Intrinsic genomic incompatibility between S. aethnensis and S. chrysanthemifolius revealed by TRD across multiple genomic regions in early-generation hybrids is likely to impact the genetic structure of the natural hybrid zone on Mount Etna by limiting introgression and promoting divergence across the genome.     

Genome-Wide Association Analyses for Fatty Acid Composition in Porcine Muscle and Abdominal Fat Tissues

Fatty acid composition is an important phenotypic trait in pigs as it affects nutritional, technical and sensory quality of pork. Here, we reported a genome-wide association study (GWAS) for fatty acid composition in the longissimus muscle and abdominal fat tissues of 591 White Duroc×Erhualian F₂ animals and in muscle samples of 282 Chinese Sutai pigs. A total of 46 loci surpassing the suggestive significance level were identified on 15 pig chromosomes (SSC) for 12 fatty acids, revealing the complex genetic architecture of fatty acid composition in pigs. Of the 46 loci, 15 on SSC5, 7, 14 and 16 reached the genome-wide significance level. The two most significant SNPs were ss131535508 (P = 2.48×10⁻²⁵) at 41.39 Mb on SSC16 for C20∶0 in abdominal fat and ss478935891 (P = 3.29×10⁻¹³) at 121.31 Mb on SSC14 for muscle C18∶0. A meta-analysis of GWAS identified 4 novel loci and enhanced the association strength at 6 loci compared to those evidenced in a single population, suggesting the presence of common underlying variants. The longissimus muscle and abdominal fat showed consistent association profiles at most of the identified loci and distinct association signals at several loci. All loci have specific effects on fatty acid composition, except for two loci on SSC4 and SSC7 affecting multiple fatness traits. Several promising candidate genes were found in the neighboring regions of the lead SNPs at the genome-wide significant loci, such as SCD for C18∶0 and C16∶1 on SSC14 and ELOVL7 for C20∶0 on SSC16. The findings provide insights into the molecular basis of fatty acid composition in pigs, and would benefit the final identification of the underlying mutations.     

The genomics of incompatibility factors and sex determination in hybridizing species of Cottus (Pisces)

Cottus rhenanus and Cottus perifretum have formed hybrid lineages and narrow hybrid zones that can be best explained through the action of natural selection. However, the underlying selective forces as well as their genomic targets are not well understood. This study identifies genomic regions in the parental species that cause hybrid incompatibilities and tests whether these manifest in a sex-specific manner to learn about processes that affect natural hybridization in Cottus. Interspecific F₂ crosses were analyzed for 255 markers for genetic mapping and to detect transmission distortion as a sign for genetic incompatibilities. The Cottus map consists of 24 linkage groups with a total length of 1575.4 cM. A male heterogametic (XY) sex determination region was found on different linkage groups in the two parental species. Genetic incompatibilities were incomplete, varied among individuals and populations and were not associated with the heterogametic sex. The variance between populations and individuals makes it unlikely that there are species-specific incompatibility loci that could affect the gene pool of natural hybrids in a simple and predictable way. Conserved synteny with sequenced fish genomes permits to genetically study the Cottus genome through the transfer of genomic information from the model fish species. Homology relationships of candidate genomic regions in Cottus indicate that sex determination is not based on the same genomic regions found in other fish species. This suggests a fast evolutionary turnover of the genetic basis of sex determination that, together with the small size of the heterogametic regions, may contribute to the absence of fitness effects related to the Haldane''s rule.     

Frameshift Suppression in SACCHAROMYCES CEREVISIAE. II. Genetic Properties of Group II Suppressors

Suppressors of ICR-induced mutations that exhibit behavior similar to bacterial frameshift suppressors have been identified in the yeast Saccharomyces cerevisiae. The yeast suppressors have been divided into two groups. One of these groups (Group II: SUF1, SUF3, SUF4, SUF5 and SUF6) appears to include a set of informational suppressors in which the vehicle of suppression is glycyl-tRNA. Some of the genetic properties of Group II suppressors are described in this communication.——Corevertants of the Group II frameshift mutations his4–519 and leu2–3 have been characterized to determine the spectrum of reversion events induced by the frameshift mutagen ICR-170. Seventythree ICR-induced corevertants were analyzed. With the exception of one corevertant, which carried an allele of SUF1, all carried alleles of SUF3 or SUF5. SUF1, SUF3, SUF4 and SUF6 were represented among spontaneous and UV-induced corevertants. In the course of these experiments one of the suppressors was mapped. SUF5, the probable structural gene for tRNA^GLY1, is located between ade2 and ade9 on chromosome XV.——SUF1, SUF4 and SUF6 have novel properties and comprise a distinct subset of suppressors. Although these suppressors show no genetic linkage to each other, they share several common features including lethality in haploid pairwise combinations, reduced tRNA^GLY3 isoacceptor activity and increased efficiency of suppression in strains carrying the cytoplasmically inherited [PSI] element. In addition, strains carrying SUF1, SUF4 or SUF6 are phenotypically unstable and give rise to mitotic Suf⁺ segregants at high frequency. These segregants invariably contain a linked, second-site mutation that maps in or adjacent to the suppressor gene itself. Strains carrying any of these suppressors also give rise to mitotic segregants that exhibit enhanced efficiency of suppression; mutations responsible for this phenotype map at two loci, upf1 and upf2. These genes show no genetic linkage to any of the Group II suppressors.——Methods that permit positive selection for mutants with decreased or enhanced efficiency of suppression have been devised in order to examine large numbers of variants. The importance of these interacting mutants is underscored by their potential utility in studying suppressor function at the molecular level.     

DNA Methylation in an Enhancer Region of the FADS Cluster Is Associated with FADS Activity in Human Liver

Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20∶4, n-6), eicosapentaenoic acid (EPA; 20∶5, n-3) and docosahexaenoic acid (DHA; 22∶6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18∶2, n-6) to AA and α-linolenic acid (ALA, 18∶3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5′ to 5′) in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ∼15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95×10⁻⁴⁶) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities.     

Evidence of the accumulation of allele-specific non-synonymous substitutions in the young region of recombination suppression within the mating-type chromosomes of Neurospora tetrasperma

Currently, little is known about the origin and early evolution of sex chromosomes. This is largely due to the fact that ancient non-recombining sex chromosomes are highly degenerated, and thus provide little information about the early genomic events in their evolution. The Neurospora tetrasperma mating-type (mat) chromosomes contain a young (<6 Mya) and large region (>6.6 Mb) of suppressed recombination, thereby providing a model system to study early stages of sex chromosome evolution. Here, we examined alleles of 207 genes located on the N. tetrasperma mat a and mat A chromosomes to test for signs of genomic alterations at the protein level in the young region of recombination suppression. We report that the N. tetrasperma mat a and mat A chromosomes have each independently accumulated allele-specific non-synonymous codon substitutions in a time-dependent, and gene-specific manner in the recombinationally suppressed region. In addition, examination of the ratio (ω) of non-synonymous substitutions (dN) to synonymous substitutions (dS) using maximum likelihood analyses, indicates that such changes are associated with relaxed purifying selection, a finding consistent with genomic degeneration. We also reveal that sex specific biases in mutation rates or selection pressures are not necessary for genomic alterations in sex chromosomes, and that recombination suppression in itself is sufficient to explain these results. The present findings extend our current understanding of genomic events associated within the young region of recombination suppression in these fungal sex-regulating chromosomes.     

Live Birth Sex Ratio after In Vitro Fertilization and Embryo Transfer in China - An Analysis of 121,247 Babies from 18 Centers

In order to study the impact of procedures of IVF/ICSI technology on sex ratio in China, we conducted this multi-center retrospective study including 121,247 babies born to 93,895 women in China. There were 62,700 male babies and 58,477 female babies, making the sex ratio being 51.8% (Male: Female  = 107∶100). In univariate logistic regression analysis, sex ratio was imbalance toward females of 50.3% when ICSI was preformed compared to 47.7% when IVF was used (P<0.01). The sex ratio in IVF/ICSI babies was significantly higher toward males in transfers of blastocyst (54.9%) and thawed embryo (52.4%) when compared with transfers of cleavage stage embryo (51.4%) and fresh embryo (51.5%), respectively. Multiple delivery was not associated with sex ratio. However, in multivariable logistic regression analysis after controlling for related factors, only ICSI (adjusted OR = 0.90, 95%CI: 0.88–0.93; P<0.01) and blastocyst transfer (adjusted OR = 1.14, 95% CI: 1.09–1.20; P<0.01) were associated with sex ratio in IVF/ICSI babies. In conclusion, the live birth sex ratio in IVF/ICSI babies was influenced by the use of ICSI, which may decrease the percentage of male offspring, or the use of blastocyst transfer, which may increase the percentage of male offspring.     

In-Silico Analysis of Inflammatory Bowel Disease (IBD) GWAS Loci to Novel Connections

Genome-wide association studies (GWASs) for many complex diseases, including inflammatory bowel disease (IBD), produced hundreds of disease-associated loci—the majority of which are noncoding. The number of GWAS loci is increasing very rapidly, but the process of translating single nucleotide polymorphisms (SNPs) from these loci to genomic medicine is lagging. In this study, we investigated 4,734 variants from 152 IBD associated GWAS loci (IBD associated 152 lead noncoding SNPs identified from pooled GWAS results + 4,582 variants in strong linkage-disequilibrium (LD) (r² ≥0.8) for EUR population of 1K Genomes Project) using four publicly available bioinformatics tools, e.g. dbPSHP, CADD, GWAVA, and RegulomeDB, to annotate and prioritize putative regulatory variants. Of the 152 lead noncoding SNPs, around 11% are under strong negative selection (GERP++ RS ≥2); and ~30% are under balancing selection (Tajima’s D score >2) in CEU population (1K Genomes Project)—though these regions are positively selected (GERP++ RS <0) in mammalian evolution. The analysis of 4,734 variants using three integrative annotation tools produced 929 putative functional SNPs, of which 18 SNPs (from 15 GWAS loci) are in concordance with all three classifiers. These prioritized noncoding SNPs may contribute to IBD pathogenesis by dysregulating the expression of nearby genes. This study showed the usefulness of integrative annotation for prioritizing fewer functional variants from a large number of GWAS markers.     

Cytogenetic Characterization and AFLP-Based Genetic Linkage Mapping for the Butterfly Bicyclus anynana,Covering All 28 Karyotyped Chromosomes

Background

The chromosome characteristics of the butterfly Bicyclus anynana, have received little attention, despite the scientific importance of this species. This study presents the characterization of chromosomes in this species by means of cytogenetic analysis and linkage mapping.

Methodology/Principal Findings

Physical genomic features in the butterfly B. anynana were examined by karyotype analysis and construction of a linkage map. Lepidoptera possess a female heterogametic W-Z sex chromosome system. The WZ-bivalent in pachytene oocytes of B. anynana consists of an abnormally small, heterochromatic W-chromosome with the Z-chromosome wrapped around it. Accordingly, the W-body in interphase nuclei is much smaller than usual in Lepidoptera. This suggests an intermediate stage in the process of secondary loss of the W-chromosome to a ZZ/Z sex determination system. Two nucleoli are present in the pachytene stage associated with an autosome and the WZ-bivalent respectively. Chromosome counts confirmed a haploid number of n = 28. Linkage mapping had to take account of absence of crossing-over in females, and of our use of a full-sib crossing design. We developed a new method to determine and exclude the non-recombinant uninformative female inherited component in offspring. The linkage map was constructed using a novel approach that uses exclusively JOINMAP-software for Lepidoptera linkage mapping. This approach simplifies the mapping procedure, avoids over-estimation of mapping distance and increases the reliability of relative marker positions. A total of 347 AFLP markers, 9 microsatellites and one single-copy nuclear gene covered all 28 chromosomes, with a mapping distance of 1354 cM. Conserved synteny of Tpi on the Z-chromosome in Lepidoptera was confirmed for B. anynana. The results are discussed in relation to other mapping studies in Lepidoptera.

Conclusions/Significance

This study adds to the knowledge of chromosome structure and evolution of an intensively studied organism. On a broader scale it provides an insight in Lepidoptera sex chromosome evolution and it proposes a simpler and more reliable method of linkage mapping than used for Lepidoptera to date.     

DNA transposon dynamics in populations of Daphnia pulex with and without sex

We investigate the role of recombination in transposable element (TE) proliferation in the cyclical parthenogen, Daphnia pulex. Recombination provides a mechanism by which the rate of both TE gain and loss can be accelerated, a duality that has long intrigued many biologists interested in the influence of sex on mutation accumulation. We compared TE loads among populations of D. pulex where sex occurs regularly (cyclical parthenogens or ‘sexuals’) with those in which the ability to reproduce sexually has been completely lost (obligate ‘asexuals’) for six different families of DNA transposons. Transposon display assays showed that sexuals have more TEs than asexuals, contrary to the expectations under Muller''s ratchet but consistent with the idea that sex facilitates TE spread. Sexuals also exhibit higher insertion site polymorphism among lineages, as predicted because recombination accelerates rates of loss and gain. Asexuals, however, have proportionally more singletons (loci occupied in a single isolate), which differs from previous studies where selfing and outcrossing were used as a proxy for high and low recombination. Our multi-element survey reveals that the impact of sex on TE proliferation is consistent among different Class II TE families and we discuss the genomic consequences of different reproductive strategies over long time periods.     

Two Distinct Categories of Focal Deletions in Cancer Genomes

One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we’ve addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors.     

The Effect of Linkage Disequilibrium and Family Relationships on the Reliability of Genomic Prediction

Although the concept of genomic selection relies on linkage disequilibrium (LD) between quantitative trait loci and markers, reliability of genomic predictions is strongly influenced by family relationships. In this study, we investigated the effects of LD and family relationships on reliability of genomic predictions and the potential of deterministic formulas to predict reliability using population parameters in populations with complex family structures. Five groups of selection candidates were simulated by taking different information sources from the reference population into account: (1) allele frequencies, (2) LD pattern, (3) haplotypes, (4) haploid chromosomes, and (5) individuals from the reference population, thereby having real family relationships with reference individuals. Reliabilities were predicted using genomic relationships among 529 reference individuals and their relationships with selection candidates and with a deterministic formula where the number of effective chromosome segments (M_e) was estimated based on genomic and additive relationship matrices for each scenario. At a heritability of 0.6, reliabilities based on genomic relationships were 0.002 ± 0.0001 (allele frequencies), 0.022 ± 0.001 (LD pattern), 0.018 ± 0.001 (haplotypes), 0.100 ± 0.008 (haploid chromosomes), and 0.318 ± 0.077 (family relationships). At a heritability of 0.1, relative differences among groups were similar. For all scenarios, reliabilities were similar to predictions with a deterministic formula using estimated M_e. So, reliabilities can be predicted accurately using empirically estimated M_e and level of relationship with reference individuals has a much higher effect on the reliability than linkage disequilibrium per se. Furthermore, accumulated length of shared haplotypes is more important in determining the reliability of genomic prediction than the individual shared haplotype length.     

Condition Dependent Effects on Sex Allocation and Reproductive Effort in Sequential Hermaphrodites

Theory predicts the optimal timing of sex change will be the age or size at which half of an individual''s expected fitness comes through reproduction as a male and half through reproduction as a female. In this way, sex allocation across the lifetime of a sequential hermaphrodite parallels the sex allocation of an outbreeding species exhibiting a 1∶1 ratio of sons to daughters. However, the expectation of a 1∶1 sex ratio is sensitive to variation in individual condition. If individuals within a population vary in condition, high-condition individuals are predicted to make increased allocations to the sex with the higher variance in reproductive success. An oft-cited example of this effect is seen in red deer, Cervus elaphus, in which mothers of high condition are more likely to produce sons, while those in low condition are more likely to produce daughters. Here, we show that individual condition is predicted to similarly affect the pattern of sex allocation, and thus the allocation of reproductive effort, in sequential hermaphrodites. High-condition sex-changers are expected to obtain more than half of their fitness in the high-payoff second sex and, as a result, are expected to reduce the allocation of reproductive effort in the initial sex. While the sex ratio in populations of sequential hermaphrodites is always skewed towards an excess of the initial sex, condition dependence is predicted to increase this effect.     

Transferability and Fine-Mapping of Genome-Wide Associated Loci for Adult Height across Human Populations

Human height is the prototypical polygenic quantitative trait. Recently, several genetic variants influencing adult height were identified, primarily in individuals of East Asian (Chinese Han or Korean) or European ancestry. Here, we examined 152 genetic variants representing 107 independent loci previously associated with adult height for transferability in a well-powered sample of 1,016 unrelated African Americans. When we tested just the reported variants originally identified as associated with adult height in individuals of East Asian or European ancestry, only 8.3% of these loci transferred (p-values≤0.05 under an additive genetic model with directionally consistent effects) to our African American sample. However, when we comprehensively evaluated all HapMap variants in linkage disequilibrium (r ²≥0.3) with the reported variants, the transferability rate increased to 54.1%. The transferability rate was 70.8% for associations originally reported as genome-wide significant and 38.0% for associations originally reported as suggestive. An additional 23 loci were significantly associated but failed to transfer because of directionally inconsistent effects. Six loci were associated with adult height in all three groups. Using differences in linkage disequilibrium patterns between HapMap CEU or CHB reference data and our African American sample, we fine-mapped these six loci, improving both the localization and the annotation of these transferable associations.     

A microsatellite-based analysis for the detection of selection on BTA1 and BTA20 in northern Eurasian cattle (Bos taurus) populations

Background

Microsatellites surrounding functionally important candidate genes or quantitative trait loci have received attention as proxy measures of polymorphism level at the candidate loci themselves. In cattle, selection for economically important traits is a long-term strategy and it has been reported that microsatellites are linked to these important loci.

Methods

We have investigated the variation of seven microsatellites on BTA1 (Bos taurus autosome 1) and 16 on BTA20, using bovine populations of typical production types and horn status in northern Eurasia. Genetic variability of these loci and linkage disequilibrium among these loci were compared with those of 28 microsatellites on other bovine chromosomes. Four different tests were applied to detect molecular signatures of selection.

Results

No marked difference in locus variability was found between microsatellites on BTA1, BTA20 and the other chromosomes in terms of different diversity indices. Average D'' values of pairwise syntenic markers (0.32 and 0.28 across BTA 1 and BTA20 respectively) were significantly (P < 0.05) higher than for non-syntenic markers (0.15). The Ewens-Watterson test, the Beaumont and Nichol''s modified frequentist test and the Bayesian F_ST-test indicated elevated or decreased genetic differentiation, at SOD1 and AGLA17 markers respectively, deviating significantly (P < 0.05) from neutral expectations. Furthermore, lnRV, lnRH and lnRθ'' statistics were used for the pairwise population comparison tests and were significantly less variable in one population relative to the other, providing additional evidence of selection signatures for two of the 51 loci. Moreover, the three Finnish native populations showed evidence of subpopulation divergence at SOD1 and AGLA17. Our data also indicate significant intergenic linkage disequilibrium around the candidate loci and suggest that hitchhiking selection has played a role in shaping the pattern of observed linkage disequilibrium.

Conclusion

Hitchhiking due to tight linkage with alleles at candidate genes, e.g. the POLL gene, is a possible explanation for this pattern. The potential impact of selective breeding by man on cattle populations is discussed in the context of selection effects. Our results also suggest that a practical approach to detect loci under selection is to simultaneously apply multiple neutrality tests based on different assumptions and estimations.     

Mendel's First Law: partisan interests and the parliament of genes

Mendel’s First Law requires explanation because of the possibility of ‘meiotic drivers’, genes that distort fair segregation for selfish gain. The suppression of drive, and the restoration of fair segregation, is often attributed to genes at loci unlinked to the drive locus—such genes cannot benefit from drive but do suffer its associated fitness costs. However, selection can also favour suppressors at loci linked to the drive locus, raising the question of whether suppression of drive usually comes from linked or unlinked loci. Here, I study linked and unlinked suppression in a two-locus model with initial stable polymorphism at the drive locus. I find that the invasion rate of suppressors is a decreasing function of the recombination fraction between the drive and suppressor loci. Surprisingly, the relative likelihood of unlinked vs. linked suppression increases with the strength of drive and is insensitive to the fitness costs of the driver allele. I find that the chromosomal position of the driver influences how rapidly it is suppressed, with a driver in the middle of a chromosome suppressed more rapidly than a driver near the tip. When drive is strong, only a small number of chromosomes are required for suppression usually to derive from unlinked loci. In contrast, when drive is weak, and especially when suppressor alleles are associated with fitness costs, suppression will usually come from linked loci unless the genome comprises many chromosomes.Subject terms: Evolutionary genetics, Population genetics