Relative Extended Haplotype Homozygosity Research Articles

Positive selection signatures in Anqing six-end-white pig population based on reduced-representation genome sequencing data.

Anqing six-end-white (AQ) pig performs well on resistance to coarse fodder and disease, reproduction and meat quality, offering high potential for exploitation. Environmental conditions and strict selections from local farmers have cultivated the AQ pig to be an outstanding and unique local pig breed. Thus we aim to detect genetic positive selection signatures within the AQ pig population to explore underlying genetic mechanisms. A relative extended haplotype homozygosity (REHH) test was performed in the population of 79 AQ pigs to seek evidence demonstrating that selective actions have left an imprint on the whole genome. In total, 430500 REHH tests were performed on 53067 core regions with average REHH tests of 8.11, average lengths of 11.50kb and an overall length of 610.38Mb which accounted for 26.94% of the whole genome. Finally, a total of 1819 core haplotypes (P<0.01) and 586 candidate genes were obtained. These genes were mainly related to meat quality (MYOG, SNX19), resistance to disease (CRISPLD2, CD14) and reproduction traits (ERBB2, NRP2). A panel of genes within the 30 top significant REHH tests was mainly categorized to traits of meat quality and disease resistance. Among 13 KEGG pathways, MAPK, GnRH and Oxytocin signaling pathways, associated with the biological processes of crucial economic traits, were noteworthy. The excellent characteristics of the AQ pig benefited from the combination of natural and human factors. We provide a sketch map that shows the distribution of selection footprints on the whole genome of AQ pig and found potential genes for future studies.

Selection signatures in candidate genes and QTL for reproductive traits in Nellore heifers

The identification of selection signature genes may help to detect genomic regions that underwent artificial selection and contributed to phenotypic diversity. The aim of this study, therefore, was to detect selection signatures in candidate genes and quantitative trait locus (QTL) for reproductive traits in a Nellore population being selected for sexual precocity. A total of 2035 Nellore heifers, sourced from breeding programs focused on sexual precocity, were used. Candidate genes and some specific QTL related to reproductive traits were chosen based on published literature and Animal QTL databases, respectively, for investigation whether these regions were affected by selection. Selection signature DNA sequences were detected in the selected regions using the extended haplotype homozygosity (EHH) and relative extended haplotype homozygosity (REHH) methods. From 22,241 single nucleotide polymorphisms (SNPs) located in the candidate genes and QTL, 17,312 SNPs generated 2756 haplotype blocks. A total of 7518 EHH tests were analyzed using haplotypes with a frequency of more than 25%, for which there were 39 tests that were significant for REHH (P<0.01). Selection signature DNA sequences were detected that contained several QTLs for important reproductive traits in cattle, suggesting that reproductive traits may have been affected by selection for sexual precocity in this population. Forty-six genes were located in the selection signature regions, whereas 24 genes participated in important biological processes or pathways that may underlie sexual precocity. These results indicate there are possible molecular mechanisms related to sexual precocity in the Nellore breed.

Genome-wide detection of selective signatures in a Duroc pig population

The Duroc pig has high adaptability and feeding efficiency, making it one of the most popular pig breeds worldwide. Over long periods of natural and artificial selection, genetic footprints, i.e., selective signatures, were left in the genome. In this study, a Duroc pig population (n=715) was genotyped with the Porcine SNP60K Bead Chip and the GeneSeek Genomic Profiler (GGP) Porcine Chip. The relative extended haplotype homozygosity (REHH) method was used for selective signature detection in a subset of the population (n=368), selected to represent a balanced family structure. In total, 154 significant core regions were detected as selective signatures (P<0.01), some of which overlap with previously reported quantitative trait loci associated with several economically important traits, including average daily gain and backfat thickness. Genome annotation for these significant core regions revealed a variety of interesting candidate genes including GATA3, TAF3, ATP5C1, and FGF1. These genes were functionally related to anterior/posterior pattern specification, phosphatidylinositol 3-kinase signaling, embryonic skeletal system morphogenesis, and oxidation-reduction processes. This research provides knowledge for the study of selection mechanisms and breeding practices in Duroc and other pigs.

A genome-wide detection of selection signatures in conserved and commercial pig breeds maintained in Poland

BackgroundIdentification of selection signatures can provide a direct insight into the mechanism of artificial selection and allow further disclosure of the candidate genes related to the animals’ phenotypic variation. Domestication and subsequent long-time selection have resulted in extensive phenotypic changes in domestic pigs, involving a number of traits, like behavior, body composition, disease resistance, reproduction and coat color. In this study, based on genotypes obtained from PorcineSNP60 Illumina assay we attempt to detect both diversifying and within-breed selection signatures in 530 pigs belonging to four breeds: Polish Landrace, Puławska, Złotnicka White and Złotnicka Spotted, of which the last three are a subject of conservative breeding and substantially represent the native populations.ResultsA two largely complementary statistical methods were used for signatures detection, including: pairwise FST and relative extended haplotype homozygosity (REHH) test. Breed-specific diversifying selection signals included several genes involved in processes connected with fertility, growth and metabolism which are potentially responsible for different phenotypes of the studied breeds. The diversifying selection signals also comprised PPARD gene that was previously found to have a large effect on the shape of the external ear in pigs or two genes encoding neuropeptide Y receptors (Y2 and Y5) involved in fat deposition and stress response which are important features differentiating the studied breeds. REHH statistics allowed detecting several within-breed selection signatures overlapping with genes connected with a range of functions including, among others: metabolic pathways, immune system response or implantation and development of the embryo.ConclusionsThe study provides many potential candidate genes with implication for traits selected in the individual breeds and gives strong basis for further studies aiming at identification of sources of variation among the studied pig breeds.

Genomic signatures reveal selection of characteristics within and between Meishan pig populations.

The Chinese Meishan pig breed is well known for its high prolificacy. Moreover, this breed can be divided into three types based on their body size: big Meishan, middle Meishan (MMS) and small Meishan (SMS) pigs. Few studies have reported on the genetic signatures of Meishan pigs, particularly on a genome-wide scale. Exploring for genetic signatures could be quite valuable for revealing the genetic architecture of phenotypic variation. Thus, we performed research in two parts based on the genome reducing and sequencing data of 143 Meishan pigs (74 MMS pigs, 69 SMS pigs). First, we detected the selection signatures among all Meishan pigs studied using the relative extended haplotype homozygosity test. Second, we detected the selection signatures between MMS and SMS pigs using the cross-population extended haplotype homozygosity and FST methods. A total of 111398 SNPs were identified from the sequenced genomes. In the population analysis, the most significant genes were associated with the mental development (RGMA), reproduction (HDAC4, FOXL2) and lipid metabolism (ACACB). From the cross-population analysis, we detected genes related to body weight (SPDEF, PACSIN1) in both methods. We suggest that rs341373351, located within the PACSIN1 gene, might be the causal variant. This study may have achieved consistency between selection signatures and characteristics within and between Meishan pig populations. These findings can provide insight into investigating the molecular background of high prolificacy and body size in pig.

Genome-wide scan and analysis of positive selective signatures in Dwarf Brown-egg Layers and Silky Fowl chickens

Chinese domestic chickens have been routinely subjected to artificial selection for the production of meats and eggs. Selection results in distinctive signatures in the genome that can reveal the genes underlying phenotypes of interest to breeders. In this study, we used the Chicken60K SNP chip to analyze DNA from Dwarf Brown-egg Layers (DB, n = 203) and Silky Fowls (SF, n = 181) and then examined the relative extended haplotype homozygosity (REHH) and fixation index (FST) to detect selection signatures. Since population structure analysis showed that SF was stratified into 2 subpopulations (SF1 and SF2), we removed the 20 SF1 chickens, and the remaining individuals (DB and SF2) were scanned for genome-wide selection signatures. A total of 939 selection signatures, including 446 candidate genes, were found to be potential selection targets using the FST test. REHH analysis identified 93 and 128 core regions, including 112 and 181 genes, in DB and SF2, respectively. Among the candidate genes, domestication-related genes such as NELL1 were found. After comparing the candidate genes with the Animal QTL database, we identified additional genes possibly associated with growth, reproduction, egg laying, and immune response, including GRHL3, CDK1, AKT1, and KMD3A. Functional enrichment analysis suggests that genes associated with muscle development have undergone positive selection. Our findings provide a genome-wide selection signature draft for DB and SF, and establish a resource that can be exploited in chicken breeding programs to manipulate the genes that underlie desired phenotypes.

Long-term selection for litter size in swine results in shifts in allelic frequency in regions involved in reproductive processes.

High-density genotype data were analyzed in three lines of swine that express substantial variation in sow fertility to uncover regions of the genome potentially influenced during selection for litter size traits. The experimental lines examined include the Nebraska Index Line (NIL), which has been subjected to long-term selection for litter size; a control line derived from the same population that founded NIL; and a commercial Duroc × Hampshire (D×H) population, in which no selection for litter size was practiced. Regions of the genome potentially affected by selection for litter size traits in NIL were determined by multiple lines of evidence, including altered allelic frequency compared to the other lines, loss of heterozygosity and relative extended haplotype homozygosity. Additionally, a genome-wide association study for litter size traits was conducted in a population based on NIL and commercial maternal line genetics. Several genomic regions identified as putative signatures of selection overlapped with QTL for litter size traits. One of these regions, located on SSC2 (13-14Mb), includes the candidate gene P2X3R, which plays a role in implantation and sustained release of hormones associated with reproductive processes. Sequencing identified synonymous SNPs in P2X3R that are fixed in NIL but polymorphic with nearly equal frequencies in the D×H line, indicating a potential role of P2X3R in sow fertility. These results suggest that data derived from these lines can help to uncover and understand a portion of the genetic variance associated with fertility traits in swine.

A genome scan of recent positive selection signatures in three sheep populations

Domesticated sheep have been exposed to artificial selection for the production of fiber, meat, and milk as well as to natural selection. Such selections are likely to have imposed distinctive selection signatures on the sheep genome. Therefore, detecting selection signatures across the genome may help elucidate mechanisms of selection and pinpoint candidate genes of interest for further investigation. Here, detection of selection signatures was conducted in three sheep breeds, Sunite (n=66), German Mutton (n=159), and Dorper (n=93), using the Illumina OvineSNP50 Genotyping BeadChip array. Each animal provided genotype information for 43 273 autosomal single nucleotide polymorphisms (SNPs). We adopted two complementary haplotype-based statistics of relative extended haplotype homozygosity (REHH) and the cross-population extended haplotype homozygosity (XP-EHH) tests. In total, 707, 755, and 438 genomic regions subjected to positive selection were identified in Sunite, German Mutton, and Dorper sheep, respectively, and 42 of these regions were detected using both REHH and XP-EHH analyses. These genomic regions harbored many important genes, which were enriched in gene ontology terms involved in muscle development, growth, and fat metabolism. Fourteen of these genomic regions overlapped with those identified in our previous genome-wide association studies, further indicating that these genes under positive selection may underlie growth developmental traits. These findings contribute to the identification of candidate genes of interest and aid in understanding the evolutionary and biological mechanisms for controlling complex traits in Chinese and western sheep.

TheCYP2C19Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers withCYP2C19*35andCYP2C19*2Alleles

CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 Genomes project (http://browser.1000genomes.org/index.html) indicated rs12769205 is in linkage disequilibrium with rs4244285 on CYP2C19*2, but found alone on CYP2C19*35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this single nucleotide polymorphism (SNP) alone leads to exon 2B and decreases CYP2C19 canonical mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19*2/*2 and *1/*35 liver microsomes with an exon 2 probe. However, an exon 4 probe, downstream from rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205, demonstrating rs12769205 alone can lead to complete loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205 and rs4244285 (CYP2C19*2/*2), but with little effect on mephenytoin disposition of CYP2C19*1/*2, CYP2C19*1/*3, or CYP2C19*1/*35 heterozygous alleles. Extended haplotype homozygosity tests of the HapMap Yorubans (YRI) showed both haplotypes carrying rs12769205 (CYP2C19*35 and CYP2C19*2) are under significant natural selection, with CYP2C19*35 having a higher relative extended haplotype homozygosity score. The phylogenetic tree of the YRI CYP2C19 haplotypes revealed rs12769205 arose first on CYP2C19*35 and that rs4244285 was added later, creating CYP2C19*2. In conclusion, rs12769205 is the ancestral polymorphism leading to aberrant splicing of CYP2C19*35 and CYP2C19*2 alleles in liver.

A novel candidate region for genetic adaptation to high altitude in Andean populations.

Humans living at high altitude (≥2,500 meters above sea level) have acquired unique abilities to survive the associated extreme environmental conditions, including hypoxia, cold temperature, limited food availability and high levels of free radicals and oxidants. Long-term inhabitants of the most elevated regions of the world have undergone extensive physiological and/or genetic changes, particularly in the regulation of respiration and circulation, when compared to lowland populations. Genome scans have identified candidate genes involved in altitude adaption in the Tibetan Plateau and the Ethiopian highlands, in contrast to populations from the Andes, which have not been as intensively investigated. In the present study, we focused on three indigenous populations from Bolivia: two groups of Andean natives, Aymara and Quechua, and the low-altitude control group of Guarani from the Gran Chaco lowlands. Using pooled samples, we identified a number of SNPs exhibiting large allele frequency differences over 900,000 genotyped SNPs. A region in chromosome 10 (within the cytogenetic bands q22.3 and q23.1) was significantly differentiated between highland and lowland groups. We resequenced ~1.5 Mb surrounding the candidate region and identified strong signals of positive selection in the highland populations. A composite of multiple signals like test localized the signal to FAM213A and a related enhancer; the product of this gene acts as an antioxidant to lower oxidative stress and may help to maintain bone mass. The results suggest that positive selection on the enhancer might increase the expression of this antioxidant, and thereby prevent oxidative damage. In addition, the most significant signal in a relative extended haplotype homozygosity analysis was localized to the SFTPD gene, which encodes a surfactant pulmonary-associated protein involved in normal respiration and innate host defense. Our study thus identifies two novel candidate genes and associated pathways that may be involved in high-altitude adaptation in Andean populations.

Relative extended haplotype homozygosity signals across breeds reveal dairy and beef specific signatures of selection.

BackgroundA number of methods are available to scan a genome for selection signatures by evaluating patterns of diversity within and between breeds. Among these, “extended haplotype homozygosity” (EHH) is a reliable approach to detect genome regions under recent selective pressure. The objective of this study was to use this approach to identify regions that are under recent positive selection and shared by the most representative Italian dairy and beef cattle breeds.ResultsA total of 3220 animals from Italian Holstein (2179), Italian Brown (775), Simmental (493), Marchigiana (485) and Piedmontese (379) breeds were genotyped with the Illumina BovineSNP50 BeadChip v.1. After standard quality control procedures, genotypes were phased and core haplotypes were identified. The decay of linkage disequilibrium (LD) for each core haplotype was assessed by measuring the EHH. Since accurate estimates of local recombination rates were not available, relative EHH (rEHH) was calculated for each core haplotype. Genomic regions that carry frequent core haplotypes and with significant rEHH values were considered as candidates for recent positive selection. Candidate regions were aligned across to identify signals shared by dairy or beef cattle breeds. Overall, 82 and 87 common regions were detected among dairy and beef cattle breeds, respectively. Bioinformatic analysis identified 244 and 232 genes in these common genomic regions. Gene annotation and pathway analysis showed that these genes are involved in molecular functions that are biologically related to milk or meat production.ConclusionsOur results suggest that a multi-breed approach can lead to the identification of genomic signatures in breeds of cattle that are selected for the same production goal and thus to the localisation of genomic regions of interest in dairy and beef production.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-015-0113-9) contains supplementary material, which is available to authorized users.

Prospection of genomic regions divergently selected in cutting line of Quarter Horses in relation to racing line

The objective of this study was to identify genomic regions divergently selected in the cutting line of Quarter Horses in relation to the racing line using SNP genotyping arrays and the relative extended haplotype homozygosity (REHH) test, an extension of EHH analysis, and the fixation index (FST) as statistical methods. A total of 188 horses of both sexes, born between 1985 and 2009 and registered with the Brazilian Association of Quarter Horse Breeders (ABQM), were used. Of these, 68 horses were from the cutting line and 120 from the racing line. On the basis of 36 genomic regions classified as selection signatures by the two statistical methods, functional annotation of genes was performed in order to identify those that might have been important during formation of the cutting line. Forty-five genes were found to be involved in biological processes related to the muscle, skeletal, cardiovascular, respiratory and nervous systems, neurotransmission, muscle energy metabolism, motor activity, vision, hearing, and cognitive function. The genes related to the last four processes are particularly interesting because these genes together may be involved in cow sense or cutting ability.

A genome-wide scan for selection signatures in Yorkshire and Landrace pigs based on sequencing data.

Pigs have experienced dramatic selection due to domestication, which has led to many different phenotypes when compared to their wild counterparts, especially in the last several decades. Currently, genome-wide scans in both cattle and humans showing positive selection footprints have been investigated. However, few studies have focused on porcine selection footprints, particularly on a genome-wide scale. Surveying for selection footprints across porcine genomes can be quite valuable for revealing the genetic mechanisms of phenotypic diversity. Here, we employed a medium sequencing depth (5–20x/site per individual, on average) approach called genotyping by genome reducing and sequencing (GGRS) to detect genome-wide selection signatures of two domestic pig breeds (Yorkshire and Landrace) that have been under intensive selection for traits of muscle development, growth and behavior. The relative extended haplotype homozygosity test, which identifies selection signatures by measuring the characteristics of haplotypes’ frequency distribution within a single population, was also applied to identify potential positively selected regions. As a result, signatures of positive selection were found in each breed. However, most selection signatures were population specific and related to genomic regions containing genes for biological categories including brain development, metabolism, growth and olfaction. Furthermore, the result of the gene set enrichment analysis indicated that selected regions of the two breeds presented a different over-representation of genes in the Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways. Our results revealed a genome-wide map of selection footprints in pigs and may help us better understand the mechanisms of selection in pig breeding.

A genome-wide scan for selection signatures in Nellore cattle.

Brazilian Nellore cattle (Bos indicus) have been selected for growth traits for over more than four decades. In recent years, reproductive and meat quality traits have become more important because of increasing consumption, exports and consumer demand. The identification of genome regions altered by artificial selection can potentially permit a better understanding of the biology of specific phenotypes that are useful for the development of tools designed to increase selection efficiency. Therefore, the aims of this study were to detect evidence of recent selection signatures in Nellore cattle using extended haplotype homozygosity methodology and BovineHD marker genotypes (>777,000 single nucleotide polymorphisms) as well as to identify corresponding genes underlying these signals. Thirty-one significant regions (P < 0.0001) of possible recent selection signatures were detected, and 19 of these overlapped quantitative trait loci related to reproductive traits, growth, feed efficiency, meat quality, fatty acid profiles and immunity. In addition, 545 genes were identified in regions harboring selection signatures. Within this group, 58 genes were associated with growth, muscle and adipose tissue metabolism, reproductive traits or the immune system. Using relative extended haplotype homozygosity to analyze high-density single nucleotide polymorphism marker data allowed for the identification of regions potentially under artificial selection pressure in the Nellore genome, which might be used to better understand autozygosity and the effects of selection on the Nellore genome.

Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution

BackgroundCytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated.We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models.ResultsBifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at −29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity < = 0.037, p <0.001.ConclusionsWe found some evidence that the slow metabolizing allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices.

Prospection of genomic regions divergently selected in racing line of Quarter Horses in relation to cutting line

Selection of Quarter Horses for different purposes has led to the formation of lines, including racing and cutting horses. The objective of this study was to identify genomic regions divergently selected in racing line of Quarter Horses in relation to cutting line applying relative extended haplotype homozygosity (REHH) analysis, an extension of extended haplotype homozygosity (EHH) analysis, and the fixation index (FST) statistic. A total of 188 horses of both sexes, born between 1985 and 2009 and registered at the Brazilian Association of Quarter Horse Breeders, including 120 of the racing line and 68 of the cutting line, were genotyped using single nucleotide polymorphism arrays. On the basis of 27 genomic regions identified as selection signatures by REHH and FST statistics, functional annotations of genes were made in order to identify those that could have been important during formation of the racing line and that could be used subsequently for the development of selection tools. Genes involved in muscle growth (n=8), skeletal growth (n=10), muscle energy metabolism (n=15), cardiovascular system (n=14) and nervous system (n=23) were identified, including the FKTN, INSR, GYS1, CLCN1, MYLK, SYK, ANG, CNTFR and HTR2B.

Evidence of Positive Selection for a Glycogen Synthase (GYS1) Mutation in Domestic Horse Populations

A dominantly inherited gain-of-function mutation in the glycogen synthase (GYS1) gene, resulting in excess skeletal muscle glycogen, has been identified in more than 30 horse breeds. This mutation is associated with the disease Equine Polysaccharide Storage Myopathy Type 1, yet persists at high frequency in some breeds. Under historical conditions of daily work and limited feed, excess muscle glycogen may have been advantageous, driving the increase in frequency of this allele. Fine-scale DNA sequencing in 80 horses and genotype assays in 279 horses revealed a paucity of haplotypes carrying the mutant allele when compared with the wild-type allele. Additionally, we found increased linkage disequilibrium, measured by relative extended haplotype homozygosity, in haplotypes carrying the mutation compared with haplotypes carrying the wild-type allele. Coalescent simulations of Belgian horse populations demonstrated that the high frequency and extended haplotype associated with the GYS1 mutation were unlikely to have arisen under neutrality or due to population demography. In contrast, in Quarter Horses, elevated relative extended haplotype homozygosity was associated with multiple haplotypes and may be the result of recent population expansion or a popular sire effect. These data suggest that the GYS1 mutation underwent historical selection in the Belgian, but not in the Quarter Horse.

Runs of homozygosity associated with speech delay in autism in a taiwanese han population: evidence for the recessive model.

Runs of homozygosity (ROH) may play a role in complex diseases. In the current study, we aimed to test if ROHs are linked to the risk of autism and related language impairment. We analyzed 546,080 SNPs in 315 Han Chinese affected with autism and 1,115 controls. ROH was defined as an extended homozygous haplotype spanning at least 500 kb. Relative extended haplotype homozygosity (REHH) for the trait-associated ROH region was calculated to search for the signature of selection sweeps. Totally, we identified 676 ROH regions. An ROH region on 11q22.3 was significantly associated with speech delay (corrected p = 1.73×10−8). This region contains the NPAT and ATM genes associated with ataxia telangiectasia characterized by language impairment; the CUL5 (culin 5) gene in the same region may modulate the neuronal migration process related to language functions. These three genes are highly expressed in the cerebellum. No evidence for recent positive selection was detected on the core haplotypes in this region. The same ROH region was also nominally significantly associated with speech delay in another independent sample (p = 0.037; combinatorial analysis Stouffer’s z trend = 0.0005). Taken together, our findings suggest that extended recessive loci on 11q22.3 may play a role in language impairment in autism. More research is warranted to investigate if these genes influence speech pathology by perturbing cerebellar functions.

DHCR7 mutations linked to higher vitamin D status allowed early human migration to Northern latitudes

BackgroundVitamin D is essential for a wide range of physiological processes including immune function and calcium homeostasis. Recent investigations have identified candidate genes which are strongly linked to concentrations of 25-hydroxyvitamin D. Since there is insufficient UVB radiation to induce year-round cutaneous synthesis of vitamin D at latitudes distant from the equator it is likely that these genes were subject to forces of natural selection. We used the fixation index (FST) to measure differences in allele frequencies in 993 individuals from ten populations to identify the presence of evolutionary selection in genes in the vitamin D pathway. We then explored the length of haplotypes in chromosomes to confirm recent positive selection.ResultsWe find evidence of positive selection for DHCR7, which governs availability of 7-dehydrocholesterol for conversion to vitamin D3 by the action of sunlight on the skin. We show that extended haplotypes related to vitamin D status are highly prevalent at Northern latitudes (Europe 0.72, Northeast Asia 0.41). The common DHCR7 haplotype underwent a recent selective sweep in Northeast Asia, with relative extended haplotype homozygosity of 5.03 (99th percentile). In contrast, CYP2R1, which 25-hydroxylates vitamin D, is under balancing selection and we found no evidence of recent selection pressure on GC, which is responsible for vitamin D transport.ConclusionsOur results suggest that genetic variation in DHCR7 is the major adaptation affecting vitamin D metabolism in recent evolutionary history which helped early humans to avoid severe vitamin D deficiency and enabled them to inhabit areas further from the equator.

Natural selection among Eurasians at genomic regions associated with HIV-1 control

BackgroundHIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Here, we examine population differentiation and haplotype patterns at several loci identified through genome-wide association studies on HIV-1 control, as determined by viral-load setpoint, in European and African-American populations. We use genome-wide data from the Human Genome Diversity Project, consisting of 53 world-wide populations, to compare measures of FST and relative extended haplotype homozygosity (REHH) at these candidate loci to the rest of the respective chromosome.ResultsWe find that the Europe-Middle East and Europe-South Asia pairwise FST in the most strongly associated region are elevated compared to most pairwise comparisons with the sub-Saharan African group, which exhibit very low FST. We also find genetic signatures of recent positive selection (higher REHH) at these associated regions among all groups except for sub-Saharan Africans and Native Americans. This pattern is consistent with one in which genetic differentiation, possibly due to diversifying/positive selection, occurred at these loci among Eurasians.ConclusionsThese findings are concordant with those from earlier studies suggesting recent evolutionary change at immunity-related genomic regions among Europeans, and shed light on the potential genetic and evolutionary origin of population differences in HIV-1 control.