Long runs of homozygosity are enriched for deleterious variation.
Ontology highlight
ABSTRACT:
SUBMITTER: Szpiech ZA
PROVIDER: S-EPMC3710769 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
Publications
Long runs of homozygosity are enriched for deleterious variation.
Szpiech Zachary A ZA Xu Jishu J Pemberton Trevor J TJ Peng Weiping W Zöllner Sebastian S Rosenberg Noah A NA Li Jun Z JZ
American journal of human genetics 20130606 1
Exome sequencing offers the potential to study the population-genomic variables that underlie patterns of deleterious variation. Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection. The relationship between ROH and patterns of predicted deleterious variation can provide insight into the way in which these proce ...[more]
Similar Datasets
Project description:Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.
| S-EPMC6817522 | biostudies-literature
Project description:Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10-5; βFROH (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10-16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10-4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
| S-EPMC7904832 | biostudies-literature
Project description:Recent studies have highlighted the potential of analyses of genomic sharing to produce insight into the demographic processes affecting human populations. We study runs of homozygosity (ROH) in 18 Jewish populations, examining these groups in relation to 123 non-Jewish populations sampled worldwide.By sorting ROH into 3 length classes (short, intermediate, and long), we evaluate the impact of demographic processes on genomic patterns in Jewish populations.We find that the portion of the genome appearing in long ROH - the length class most directly related to recent consanguinity - closely accords with data gathered from interviews during the 1950s on frequencies of consanguineous unions in various Jewish groups.The high correlation between 1950s consanguinity levels and coverage by long ROH explains differences across populations in ROH patterns. The dissection of ROH into length classes and the comparison to consanguinity data assist in understanding a number of additional phenomena, including similarities of Jewish populations to Middle Eastern, European, and Central and South Asian non-Jewish populations in short ROH patterns, relative lengths of identity-by-descent tracts in different Jewish groups, and the "population isolate" status of the Ashkenazi Jews.
| S-EPMC5698150 | biostudies-literature
Project description:ImportanceMutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.ObjectiveTo evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.Design, setting, and participantsCase-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.Main outcomes and measuresThe ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.ResultsThe African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers.Conclusions and relevanceTo our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
| S-EPMC4641052 | biostudies-literature
Project description:BackgroundA decline in the level of genetic diversity in livestock can result in reduced response to selection, greater incidence of genetic defects, and inbreeding depression. In this context, various metrics have been proposed to assess the level of genetic diversity in selected populations. Therefore, the main goals of this study were to: 1) investigate the population structure of 16 cattle populations from 15 different pure breeds or composite populations, which have been selected for different breeds goals; and, 2) identify and compare runs of homozygosity (ROH) and heterozygosity-enriched regions (HER) based on different single nucleotide polymorphism (SNP) panels and whole-genome sequence data (WGS), followed by functional genomic analyses.ResultsA total of 24,187 ROH were found across all cattle populations, with 55% classified in the 2-4 Mb size group. Fourteen homozygosity islands were found in five populations, where four ROH islands located on BTA1, BTA5, BTA16, and BTA19 overlapped between the Brahman (BRM) and Gyr (GIR) breeds. A functional analysis of the genes found in these islands revealed candidate genes known to play a role in the melanogenesis, prolactin signaling, and calcium signaling pathways. The correlations between inbreeding metrics ranged from 0.02 to 0.95, where the methods based on homozygous genotypes (FHOM), uniting of gametes (FUNI), and genotype additive variance (FGRM) showed strong correlations among them. All methods yielded low to moderate correlations with the inbreeding coefficients based on runs of homozygosity (FROH). For the HER, 3576 runs and 26 islands, distributed across all autosomal chromosomes, were found in regions containing genes mainly related to the immune system, indicating potential balancing selection. Although the analyses with WGS did not enable detection of the same island patterns, it unraveled novel regions not captured when using SNP panel data.ConclusionsThe cattle populations that showed the largest amount of ROH and HER were Senepol (SEN) and Montana (MON), respectively. Overlapping ROH islands were identified between GIR and BRM breeds, indicating a possible historical connection between the populations. The distribution and pattern of ROH and HER are population specific, indicating that different breeds have experienced divergent selection processes or different genetic processes.
| S-EPMC8925140 | biostudies-literature
Project description:Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of thyroid cancer (TC). Most cancer predisposition genes identified through GWASs function in a co-dominant manner, and studies have not found evidence for recessively functioning disease loci in TC. Our study examines whether homozygosity is associated with an increased risk of TC and searches for novel recessively acting disease loci.Data from a previously conducted GWAS were used for the estimation of the proportion of phenotypic variance explained by all common SNPs, the detection of runs of homozygosity (ROH) and the determination of inbreeding to unravel their influence on TC.Inbreeding coefficients were significantly higher among cases than controls. Association on a SNP-by-SNP basis was controlled by using the false discovery rate at a level of q*?< 0.05, with 34 SNPs representing true differences in homozygosity between cases and controls. The average size, the number and total length of ROHs per person were significantly higher in cases than in controls. A total of 16 recurrent ROHs of rather short length were identified although their association with TC risk was not significant at a genome-wide level. Several recurrent ROHs harbor genes associated with risk of TC. All of the ROHs showed significant evidence for natural selection (iHS, Fst, Fay and Wu's H).Our results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner.
| S-EPMC4794977 | biostudies-literature
Project description:BackgroundRuns of homozygosity (ROH) are contiguous lengths of homozygous genotypes that are present in an individual due to parents transmitting identical haplotypes to their offspring. The extent and frequency of ROHs may inform on the ancestry of an individual and its population. Here we use high density (n?=?777,962) bi-allelic SNPs in a range of cattle breed samples to correlate ROH with the pedigree-based inbreeding coefficients and to validate subsequent analyses using 54,001 SNP genotypes. This study provides a first testing of the inference drawn from ROH through comparison with estimates of inbreeding from calculations based on the detailed pedigree data available for several breeds.ResultsAll animals genotyped on the HD panel displayed at least one ROH that was between 1-5 Mb in length with certain regions of the genome more likely to be involved in a ROH than others. Strong correlations (r?=?0.75, p?<?0.0001) existed between the pedigree-based inbreeding coefficient and a statistic based on sum of ROH of length?>?0.5 KB and suggests that in the absence of an animal's pedigree data, the extent of a genome under ROH may be used to infer aspects of recent population history even from relatively few samples.ConclusionsOur findings suggest that ROH are frequent across all breeds but differing patterns of ROH length and burden illustrate variations in breed origins and recent management.
| S-EPMC3502433 | biostudies-literature
Project description:Pedigree information was traditionally used to assess inbreeding. The availability of high-density marker panels provides an alternative to assess inbreeding, particularly in the presence of incomplete and error-prone pedigrees. Assessment of autozygosity across chromosomal segments using runs of homozygosity (ROH) has emerged as a valuable tool to estimate inbreeding due to its general flexibility and ability to quantify the chromosomal contribution to genome-wide inbreeding. Unfortunately, the identification of ROH segments is sensitive to the parameters used during the search process. These parameters are heuristically set, leading to significant variation in the results. The minimum length required to identify an ROH segment has major effects on the estimation of inbreeding and inbreeding depression, yet it is arbitrarily set. To overcome this limitation, a search algorithm to approximate mutation enrichment was developed to determine the minimum length of ROH segments. It consists of finding genome segments with significant effect differences in trait means between animals with high and low burdens of autozygous intervals with a specific length. The minimum length could be determined heuristically as the smallest interval at which a significant signal is detected. The proposed method was tested in an inbred Hereford cattle population genotyped for 30,220 SNPs. Phenotypes recorded for six traits were used for the approximation of mutation loads. The estimated minimum length was around 1 Mb for yearling weight (YW) and average daily gain (ADG) and 4 Mb for birth weight and weaning weight. These trait-specific thresholds estimated using the proposed method could be attributed to a trait-dependent effect of homozygosity. The detection of significant inbreeding effects was well aligned with the estimated thresholds, especially for YW and ADG. Although highly deleterious alleles are expected to be more frequent in recent inbreeding (long ROH), short ROH segments (<5 Mb) could contain a large number of less deleterious mutations with substantial joint effects on some traits (YW and ADG). Our results highlight the importance of accurate estimation of the ROH-based inbreeding and the necessity to consider a trait-specific minimum length threshold for the identification of ROH segments in inbreeding depression analyses. These thresholds could be determined using the proposed method provided the availability of phenotypic information.
| S-EPMC7846130 | biostudies-literature
Project description:It is long known that inbreeding increases the detrimental effects of recessive sequence variants in "Runs of Homozygosity" (ROHs). However, although the phenotypic association of ROH has been investigated for a variety of traits, the statistical power of the results often remains limited as a sufficiently high number of cases are available for only a restricted number of traits. In the present study, we aim to analyze the association of runs of homozygosity with the trait "in-group ethnic favoritism". This analysis assumes that if ethnic identity is important for an individual, that individual may tend to marry more frequently within their own group and therefore ROH are expected to increase. We hypothesize that an attitude preferring one's own ethnic group may be associated with a stronger tendency of inbreeding and, as a result, with more and longer ROHs. Accordingly, we investigated the association between the attitude to someone's own ethnicity and ROH, using the Wisconsin Longitudinal data (WLS, total N ~ 9000) as discovery data set and the Brisbane Twin data as replication data set (N ~ 8000). We find that both the number as well as the total length of homozygous segments are significantly positively associated with "in-group ethnic favoritism", independent of the method used for ROH calculation.
| S-EPMC8225526 | biostudies-literature
Project description:The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.
| S-EPMC2981575 | biostudies-literature