Declining autozygosity over time: An exploration in over 1 million individuals from three diverse cohorts.

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict FROH to decline 0.29% for every 20-year increase in birth year. We determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope = -0.058, SE = 0.015, p = 1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope = -0.001, SE = 0.008, p = 0.945). The association between autozygosity and birth year was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope = -0.011, SE = 0.008, p = 0.167), suggesting they may partially account for decreasing autozygosity over time. Overall, we demonstrate decreasing autozygosity over time in a large, modern sample and speculate that this trend can be attributed to increases in urbanization and panmixia and differences in sociodemographic processes lead to country-specific differences in the rate of decline.

Conservation management strategy impacts inbreeding and mutation load in scimitar-horned oryx.

In an age of habitat loss and overexploitation, small populations, both captive and wild, are increasingly facing the effects of isolation and inbreeding. Genetic management has therefore become a vital tool for ensuring population viability. However, little is known about how the type and intensity of intervention shape the genomic landscape of inbreeding and mutation load. We address this using whole-genome sequence data of the scimitar-horned oryx (Oryx dammah), an iconic antelope that has been subject to contrasting management strategies since it was declared extinct in the wild. We show that unmanaged populations are enriched for long runs of homozygosity (ROH) and have significantly higher inbreeding coefficients than managed populations. Additionally, despite the total number of deleterious alleles being similar across management strategies, the burden of homozygous deleterious genotypes was consistently higher in unmanaged groups. These findings emphasize the risks associated with deleterious mutations through multiple generations of inbreeding. As wildlife management strategies continue to diversify, our study reinforces the importance of maintaining genome-wide variation in vulnerable populations and has direct implications for one of the largest reintroduction attempts in the world.

Automatized detection of uniparental disomies in a large cohort.

Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome from only one parent. The detection of UPDs in sequencing data is not well established and a common gap in genetic diagnostics. We applied our in-house UPD detection pipeline to evaluate a cohort of 9212 samples, including multigene panels as well as exome sequencing data in a single, duo or trio constellation. We used the results to inform the design of our publicly available web app altAFplotter. UPDs categorized as heterodisomy, whole chromosome or segmental isodisomy were identified and validated with microsatellites, multiplex ligation-dependent probe amplification as well as Sanger sequencing. We detected 14 previously undiagnosed UPDs including nine isodisomies, four segmental isodisomies as well as one heterodisomy on chromosome 22. We characterized eight findings as potentially causative through homozygous pathogenic variants or imprinting disorders. Overall, our study demonstrates the utility of our UPD detection pipeline with our web app, altAFplotter, to reliably identify UPDs. This not only increases the diagnostic yield of cases with growth and metabolic disturbances, as well as developmental delay, but also enhances the understanding of UPDs that may be relevant for recurrence risks and genetic counseling.

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

Analysis of genetic diversity and structure of endangered Dengchuan cattle population using a single-nucleotide polymorphism chip.

This study aimed to evaluate the genetic diversity and structure within the Dengchuan cattle population and effectively protect and utilize their germplasm resources. Herein, the single-nucleotide polymorphisms (SNPs) of 100 Dengchuan cattle (46 bulls and 54 cows) were determined using the GGP Bovine 100K SNP Beadchip. The results showed that among the Dengchuan cattle, a total of 101,220 SNPs were detected, and there were 83,534 SNPs that passed quality control, of which 85.7% were polymorphic. The average genetic distance based on identity-by-state (IBS) within the conservation population of Dengchuan cattle was 0.26 ± 0.02. A total of 3,999 genome-length runs of homozygosity (ROHs) were detected in the Dengchuan cattle, with ROH lengths primarily concentrated in the range of 1-5 Mb, accounting for 87.02% of the total. The average inbreeding coefficient based on ROHs was 4.6%, within the conservation population of Dengchuan cattle, whereas it was 4.9% for bulls, and the Wright inbreeding coefficient (FIS) value was 2.4%, demonstrating a low level of inbreeding within the Dengchuan cattle population. Based on neighbor-joining tree analysis, the Dengchuan cattle could be divided into 16 families. In summary, the conservation population of Dengchuan cattle displays relatively abundant diversity and a moderate genetic relationship. Inbreeding was observed among a few individuals, but the overall inbreeding level of the population remained low. It is important to maintain this low level of inbreeding when introducing purebred bloodlines to expand the core group. This approach will ensure the long-term conservation of Dengchuan cattle germplasm resources and prevent loss of genetic diversity.

Signatures of positive selection after the introduction of genomic selection in the Finnish Ayrshire population.

The Finnish Ayrshire (FAY) belongs to the Nordic Red breeds and is characterized by high milk yield, high milk components, good fertility, and functional conformation. The FAY breeding program is based on genomic selection. Despite the benefits of selection on breeding values, autozygosity in the genome may increase due to selection, and increased autozygosity may cause inbreeding depression in selected traits. However, there is lack of studies concerning selection signatures in the FAY after genomic selection introduction. The aim of this study was to identify signatures of selection in FAY after the introduction of genomic selection. Genomic data included 45,834 SNPs. The genotyped animals were divided into 2 groups: animals born before genomic selection introduction (6,108 cows) and animals born after genomic selection introduction (47,361 cows). We identified the selection signatures using 3 complementary methods: 2 based on identification of selection signatures from runs of homozygosity (ROH) islands and one based on the decay of site-specific extended haplotype between populations at SNP sites (Rsb). In total, we identified 34 ROH islands on chromosomes 1, 3, 6, 8, 12-15, 17, 19, 22, and 26 in FAY animals born before genomic selection (between 1980 and 2011) and 30 ROH islands on chromosomes 1-3, 13-17, 22, and 25-26 in FAY animals born after genomic selection introduction (between 2015 and 2020). We additionally detected 22 ΔROH islands on chromosomes 2-3, 11, 13, 14, 16, 18, 20, and 25-26. Finally, a total of 31 Rsb regions on chromosomes 2, 3, 14, 18, 20, and 25 were identified. Based on the results, genomic selection has favored certain alleles and haplotypes on genomic regions related to traits relevant in the FAY breeding program: milk production, fertility, growth, beef production traits, and feed efficiency. Several genes related to these traits (e.g., PLA2G4A, MECR, CHUK, COX15, RICTOR, SHISA9, and SEMA4G) overlapped or partially overlapped the observed selection signature regions. The association of genotypes within these regions and their effects on traits relevant in the FAY breeding program should be studied and genetic regions undergoing selection monitored in the FAY population.

Assessment of runs of homozygosity, heterozygosity-rich regions and genomic inbreeding estimates in a subpopulation of Guzerá (Bos indicus) dual-purpose cattle.

For decades, inbreeding in cattle has been evaluated using pedigree information. Nowadays, inbreeding coefficients can be obtained using genomic information such as runs of homozygosity (ROH). The aims of this study were to quantify ROH and heterozygosity-rich regions (HRR) in a subpopulation of Guzerá dual-purpose cattle, to examine ROH and HRR islands, and to compare inbreeding coefficients obtained by ROH with alternative genomic inbreeding coefficients. A subpopulation of 1733 Guzerá animals genotyped for 50k SNPs was used to obtain the ROH and HRR segments. Inbreeding coefficients by ROH (FROH ), by genomic relationship matrix based on VanRaden's method 1 using reference allele frequency in the population (FGRM ), by genomic relationship matrix based on VanRaden's method 1 using allele frequency fixed in 0.5 (FGRM_0.5 ), and by the proportion of homozygous loci (FHOM ) were calculated. A total of 15,660 ROH were identified, and the chromosome with the highest number of ROH was BTA6. A total of 4843 HRRs were identified, and the chromosome with the highest number of HRRs was BTA23. No ROH and HRR islands were identified according to established criteria, but the regions closest to the definition of an island were examined from 64 to 67 Mb of BTA6, from 36 to 37 Mb of BTA2 and from 0.50 to 1.25 Mb of BTA23. The genes identified in ROH islands have previously been associated with dairy and beef traits, while genes identified on HRR islands have previously been associated with reproductive traits and disease resistance. FROH was equal to 0.095 ± 0.084, and its Spearman correlation with FGRM was low (0.44) and moderate-high with FHOM (0.79) and with FGRM_0.5 (0.80). The inbreeding coefficients determined by ROH were higher than other cattle breeds' and higher than pedigree-based inbreeding in the Guzerá breed obtained in previous studies. It is recommended that future studies investigate the effects of inbreeding determined by ROH on the traits under selection in the subpopulation studied.

Percutaneous removal of hardware after orthopedic surgery: Is it safe? and What are patients saying?

OBJECTIVES: To analyze our patient's complication profile and rate after removal of hardware (ROH) surgery, and survey our patients to ask their overall status and improvement in symptomatology post-operatively. DESIGN: Retrospective chart review and survey. SETTING: Academic, tertiary referral center. PATIENTS/PARTICIPANTS: 173 patients with 314 pieces of hardware. Seventy-six patients (43.9%) responded to our survey. INTERVENTION: ROH surgery. MAIN OUTCOME MEASUREMENTS: Patient demographics and complications were recorded. All patients were sent a brief 3-question survey which asked: (1) Why did you get your hardware removed? (2) How did your overall status change after ROH? (3) How did the ROH affect your stiffness, pain, swelling, and mobility? RESULTS: There were 10 complications (5.5%): 5 infections, 2 with unresolved pain, 1 hematoma, 1 chronic regional pain syndrome exacerbation, and 1 recurrent deformity. All infections were treated with oral antibiotics and improved. All other complications resolved with treatment except for the patient who developed recurrent deformity. Patients underwent ROH surgery because their doctor suggested it (76.3%) and to improve mobility (39.5%). 86.9% reported their overall status improved after ROH. They improved regarding stiffness (73.7%), pain (73.6%), swelling (61.8%), and mobility (76.3%). Similar results were seen among different implants removed. CONCLUSIONS: The majority of patients who underwent percutaneous ROH were satisfied. They reported improvement in stiffness, pain, swelling and mobility (greatest improvement). The complication rate was low (5.5%). ROH can be a meaningful operation to patients allowing them to improve their quality of life with a low complication rate. LEVEL OF EVIDENCE: Level IV.

Genome-wide assessment and mapping of inbreeding depression identifies candidate genes associated with semen traits in Holstein bulls.

BACKGROUND: The reduction in phenotypic performance of a population due to mating between close relatives is called inbreeding depression. The genetic background of inbreeding depression for semen traits is poorly understood. Thus, the objectives were to estimate the effect of inbreeding and to identify genomic regions underlying inbreeding depression of semen traits including ejaculate volume (EV), sperm concentration (SC), and sperm motility (SM). The dataset comprised ~ 330 K semen records from ~ 1.5 K Holstein bulls genotyped with 50 K single nucleotide polymorphism (SNP) BeadChip. Genomic inbreeding coefficients were estimated using runs of homozygosity (i.e., FROH > 1 Mb) and excess of SNP homozygosity (FSNP). The effect of inbreeding was estimated by regressing phenotypes of semen traits on inbreeding coefficients. Associated variants with inbreeding depression were also detected by regressing phenotypes on ROH state of the variants. RESULTS: Significant inbreeding depression was observed for SC and SM (p < 0.01). A 1% increase in FROH reduced SM and SC by 0.28% and 0.42% of the population mean, respectively. By splitting FROH into different lengths, we found significant reduction in SC and SM due to longer ROH, which is indicative of more recent inbreeding. A genome-wide association study revealed two signals positioned on BTA 8 associated with inbreeding depression of SC (p < 0.00001; FDR < 0.02). Three candidate genes of GALNTL6, HMGB2, and ADAM29, located in these regions, have established and conserved connections with reproduction and/or male fertility. Moreover, six genomic regions on BTA 3, 9, 21 and 28 were associated with SM (p < 0.0001; FDR < 0.08). These genomic regions contained genes including PRMT6, SCAPER, EDC3, and LIN28B with established connections to spermatogenesis or fertility. CONCLUSIONS: Inbreeding depression adversely affects SC and SM, with evidence that longer ROH, or more recent inbreeding, being especially detrimental. There are genomic regions associated with semen traits that seems to be especially sensitive to homozygosity, and evidence to support some from other studies. Breeding companies may wish to consider avoiding homozygosity in these regions for potential artificial insemination sires.

SNP heterozygosity, relatedness and inbreeding of whole genomes from the isolated population of the Faroe Islands.

BACKGROUND: The population of the Faroe Islands is an isolated population but very little is known about it from whole genome sequencing. The population of about 50000 people has a high incidence of rare diseases e.g., 1:300 for Primary Carnitine Deficiency. A screening programme was implemented, and eleven persons were also whole genome sequenced at x37 coverage for diagnostic purposes of those cases that were not affected by the known mutations. The purpose of our study is to utilize the high coverage data to explore the genomic variation and the ancestral history of the population. We study the SNP heterozygosity, the pairwise relatedness from kinship, the inbreeding from runs of homozygosity ROH, and we find the minor allele frequency distribution. We estimate the population ancestry and the timing of the founding event by using the whole genomes from eight consenting individuals. RESULTS: We find the number of SNPs and the heterozygosity for the eight individual samples, and for merged samples, for which we also study the relatedness. We find close relatedness between the supposedly unrelated individuals. From ROH, we interpret the high relatedness as an ancient property of the isolated population. A bottleneck event is estimated starting between years [Formula: see text] with a maximum consanguineous population in year [Formula: see text] and similarly consanguineous between years [Formula: see text]. The ancestry analysis shows the population descends from founders of [Formula: see text] European and [Formula: see text] Admixed American ancestry. A distinct clustering near the central European and British populations of the 1000 Genome Project is likely the result of the population isolation and genetic drift. The minor allele frequency distribution suggests many rare variants. CONCLUSIONS: The ancestry is mainly European while the inbreeding is higher compared to European populations and population isolates. The Faroese population has inbreeding more like ancient Europeans. We discovered a bottlenecked and consanguineous population event and estimated it starting in the 1st-4th century as compared to the oldest archaeological findings from the 4th-6th century.

Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking.

Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in humans. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co-segregated with COG3-CDG presentations. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed the loss of a single sialic acid. Western blotting on patient-derived fibroblasts revealed reduced COG3 and COG4. Further experiments showed delayed retrograde vesicular recycling in patient cells. This report adds to the knowledge of the COG-CDG network by providing collective evidence for a COG3-CDG rare disease trait and implicating a likely pathology of the disorder as the perturbation of Golgi trafficking.

Estimates of genomic inbreeding and identification of candidate regions in Beijing-You chicken populations.

Runs of homozygosity (ROHs) has become an effective method for analysing inbreeding in livestock populations. Moreover, ROHs is well-suited to detect signatures of selection via ROH islands. This study aimed to investigate the occurrence and distribution of ROHs, compare the genomic inbreeding coefficients and identify the genomic regions with high ROH frequencies in different Beijing-You chicken (BY) populations, including a random conservation population (BY_R), a pedigree conservation population (BY_P), and a commercial population obtained from the market (BY_C). Among them, BY_R in 2010 and 2019 were BY_R1 and BY_R2 respectively. A total of 27 916 ROHs were identified. The average number of ROHs per individual across the three BY populations ranged from 213 (BY_P) to 161 (BY_C), and the average length of ROHs ranged from 0.432 Mb (BY_R2) to 0.451 Mb (BY_P). The highest inbreeding coefficient calculated based on ROHs (FROH ) was 0.1 in BY_P, whereas the lowest FROH was 0.0743 in BY_C. In addition, the inbreeding coefficient of BY_R2 (FROH  = 0.0798) was higher than that of BY_R1 (FROH  = 0.0579). Furthermore, the highest proportion of long ROH fragments (>4 Mb) was observed in BY_P and BY_C. This study showed the top 10 ROH islands of each population, and these ROH islands harboured 53 genes, some of which were related to limb development, body size and immune response. These findings contribute to the understanding of genetic diversity and population demography, and might help improve breeding and conservation strategies for BY populations.

Pathogenic/likely pathogenic copy number variations and regions of homozygosity in fetal central nervous system malformations.

OBJECTIVE: To explore pathogenic/likely pathogenic copy number variations (P/LP CNVs) and regions of homozygosity (ROHs) in fetal central nervous system (CNS) malformations. METHODS: A cohort of 539 fetuses with CNS malformations diagnosed by ultrasound/MRI was retrospectively analyzed between January 2016 and December 2019. All fetuses were analyzed by chromosomal microarray analysis (CMA). Three cases with ROHs detected by CMA were subjected to whole-exome sequencing (WES). The fetuses were divided into two groups according to whether they had other structural abnormalities. The CNS phenotypes of the two groups were further classified as simple (one type) or complicated (≥ 2 types). RESULTS: (1) A total of 35 cases with P/LP CNVs were found. The incidence of P/LP CNVs was higher in the extra-CNS group [18.00% (9/50)] than in the isolated group [5.32% (26/489)] (P < 0.01), while there was no significant difference between the simpletype and complicated-type groups. (2) In the simple-type group, the three most common P/LP CNV phenotypes were holoprosencephaly, Dandy-Walker syndrome, and exencephaly. There were no P/LP CNVs associated with anencephaly, microcephaly, arachnoid cysts, ependymal cysts, or intracranial hemorrhage. (3) Only four cases with ROHs were found, and there were no cases of uniparental disomy or autosomal diseases. CONCLUSION: The P/LP CNV detection rates varied significantly among the different phenotypes of CNS malformations, although simple CNS abnormalities may also be associated with genetic abnormalities.

Analysis of the genomic landscape of inbreeding in two divergent groups of Spanish Florida goats.

The analysis of the genomic landscape of inbreeding using runs of homozygosity (ROH) patterns is becoming an interesting tool to partially understand phenotypic differences among individuals. In this study, we analysed genome-wide ROH patterns in two groups of Florida goats. We first determined the inbreeding levels of each individual by calculating ROH-based inbreeding coefficients (FROH ). Then, the individuals were divided into two groups based on FROH : high inbreeding (HI, FROH >0.1) and low inbreeding (LI, FROH <0.03). Finally, we performed an extensive in-depth analysis of ROH distribution in each group separately. We found a higher abundance of short ROH in LI, whereas long ROH was more frequent in HI. Furthermore, ROH abundance was not evenly distributed among chromosomes within groups, with some chromosomes showing larger numbers of ROH, like CHI6, CHI7 and CHI27. A different landscape was observed in recent inbreeding (ROH >8 Mb), with significant increases in CHI6, CHI11 and CHI28. Determination of genomic regions with significantly increased ROH (ROH islands-ROHi) showed 13 ROHi related to whole inbreeding and five ROHi associated with recent inbreeding analysis. Within these genomic regions, 123 and 101 genes were identified in HI and LI, respectively, including 10 and seven candidate genes previously related to production, fertility and heat resistance in goats and livestock species.

Genomic Scan for Runs of Homozygosity and Selective Signature Analysis to Identify Candidate Genes in Large White Pigs.

Large White pigs are extensively utilized in China for their remarkable characteristics of rapid growth and the high proportion of lean meat. The economic traits of pigs, comprising reproductive and meat quality traits, play a vital role in swine production. In this study, 2295 individuals, representing three different genetic backgrounds Large White pig populations were used: 500 from the Canadian line, 295 from the Danish line, and 1500 from the American line. The GeneSeek 50K GGP porcine HD array was employed to genotype the three pig populations. Firstly, genomic selective signature regions were identified using the pairwise fixation index (FST) and locus-specific branch length (LSBL). By applying a top 1% threshold for both parameters, a total of 888 candidate selective windows were identified, harbouring 1571 genes. Secondly, the investigation of regions of homozygosity (ROH) was performed utilizing the PLINK software. In total, 25 genomic regions exhibiting a high frequency of ROHs were detected, leading to the identification of 1216 genes. Finally, the identified potential functional genes from candidate genomic regions were annotated, and several important candidate genes associated with reproductive traits (ADCYAP1, U2, U6, CETN1, Thoc1, Usp14, GREB1L, FGF12) and meat quality traits (MiR-133, PLEKHO1, LPIN2, SHANK2, FLVCR1, MYL4, SFRP1, miR-486, MYH3, STYX) were identified. The findings of this study provide valuable insights into the genetic basis of economic traits in Large White pigs and may have potential use in future pig breeding programs.

Genome-wide detection of genetic structure and runs of homozygosity analysis in Anhui indigenous and Western commercial pig breeds using PorcineSNP80k data.

BACKGROUND: Runs of homozygosity (ROH) are continuous homozygous regions typically located in the DNA sequence of diploid organisms. Identifications of ROH that lead to reduced performance can provide valuable insight into the genetic architecture of complex traits. Here, we systematically investigated the population genetic structure of five Anhui indigenous pig breeds (AHIPs), and compared them to those of five Western commercial pig breeds (WECPs). Furthermore, we examined the occurrence and distribution of ROHs in the five AHIPs and estimated the inbreeding coefficients based on the ROHs (FROH) and homozygosity (FHOM). Finally, we identified genomic regions with high frequencies of ROHs and annotated candidate genes contained therein. RESULTS: The WECPs and AHIPs were clearly differentiated into two separate clades consistent with their geographical origins, as revealed by the population structure and principal component analysis. We identified 13,530 ROHs across all individuals, of which 4,555 and 8,975 ROHs were unique to AHIPs and WECPs, respectively. Most ROHs identified in our study were short (< 10 Mb) or medium (10-20 Mb) in length. WECPs had significantly higher numbers of short ROHs, and AHIPs generally had longer ROHs. FROH values were significantly lower in AHIPs than in WECPs, indicating that breed improvement and conservation programmes were successful in AHIPs. On average, FROH and FHOM values were highly correlated (0.952-0.991) in AHIPs and WECPs. A total of 27 regions had a high frequency of ROHs and contained 17 key candidate genes associated with economically important traits in pigs. Among these, nine candidate genes (CCNT2, EGR2, MYL3, CDH13, PROX1, FLVCR1, SETD2, FGF18, and FGF20) found in WECPs were related to muscular and skeletal development, whereas eight candidate genes (CSN1S1, SULT1E1, TJP1, ZNF366, LIPC, MCEE, STAP1, and DUSP) found in AHIPs were associated with health, reproduction, and fatness traits. CONCLUSION: Our findings provide a useful reference for the selection and assortative mating of pig breeds, laying the groundwork for future research on the population genetic structures of AHIPs, ultimately helping protect these local varieties.

Runs of homozygosity in Sable Island feral horses reveal the genomic consequences of inbreeding and divergence from domestic breeds.

BACKGROUND: Understanding inbreeding and its impact on fitness and evolutionary potential is fundamental to species conservation and agriculture. Long stretches of homozygous genotypes, known as runs of homozygosity (ROH), result from inbreeding and their number and length can provide useful population-level information on inbreeding characteristics and locations of signatures of selection. However, the utility of ROH for conservation is limited for natural populations where baseline data and genomic tools are lacking. Comparing ROH metrics in recently feral vs. domestic populations of well understood species like the horse could provide information on the genetic health of those populations and offer insight into how such metrics compare between managed and unmanaged populations. Here we characterized ROH, inbreeding coefficients, and ROH islands in a feral horse population from Sable Island, Canada, using ~41 000 SNPs and contrasted results with those from 33 domestic breeds to assess the impacts of isolation on ROH abundance, length, distribution, and ROH islands. RESULTS: ROH number, length, and ROH-based inbreeding coefficients (FROH) in Sable Island horses were generally greater than in domestic breeds. Short runs, which typically coalesce many generations prior, were more abundant than long runs in all populations, but run length distributions indicated more recent population bottlenecks in Sable Island horses. Nine ROH islands were detected in Sable Island horses, exhibiting very little overlap with those found in domestic breeds. Gene ontology (GO) enrichment analysis for Sable Island ROH islands revealed enrichment for genes associated with 3 clusters of biological pathways largely associated with metabolism and immune function. CONCLUSIONS: This study indicates that Sable Island horses tend to be more inbred than their domestic counterparts and that most of this inbreeding is due to historical bottlenecks and founder effects rather than recent mating between close relatives. Unique ROH islands in the Sable Island population suggest adaptation to local selective pressures and/or strong genetic drift and highlight the value of this population as a reservoir of equine genetic variation. This research illustrates how ROH analyses can be applied to gain insights into the population history, genetic health, and divergence of wild or feral populations of conservation concern.

Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.

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.

A hidden Markov model to estimate homozygous-by-descent probabilities associated with nested layers of ancestors.

Inbreeding results from the mating of related individuals and has negative consequences because it brings together deleterious variants in one individual. Genomic estimates of the inbreeding coefficients are preferred to pedigree-based estimators as they measure the realized inbreeding levels and they are more robust to pedigree errors. Several methods identifying homozygous-by-descent (HBD) segments with hidden Markov models (HMM) have been recently developed and are particularly valuable when the information is degraded or heterogeneous (e.g., low-fold sequencing, low marker density, heterogeneous genotype quality or variable marker spacing). We previously developed a multiple HBD class HMM where HBD segments are classified in different groups based on their length (e.g., recent versus old HBD segments) but we recently observed that for high inbreeding levels with many HBD segments, the estimated contributions might be biased towards more recent classes (i.e., associated with large HBD segments) although the overall estimated level of inbreeding remained unbiased. We herein propose a new model in which the HBD classification is modelled in successive nested levels with decreasing expected HBD segment lengths, the underlying exponential rates being directly related to the number of generations to the common ancestor. The non-HBD classes are now modelled as a mixture of HBD segments from later generations and shorter non-HBD segments (i.e., both with higher rates). The new model has improved statistical properties and performs better on simulated data compared to our previous version. We also show that the parameters of the model are easier to interpret and that the model is more robust to the choice of the number of classes. Overall, the new model results in an improved partitioning of inbreeding in different HBD classes and should be preferred.

Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients.

Chromosomal microarray analysis using single nucleotide polymorphism probes can detect regions of homozygosity (ROH). This confers a potential utility in revealing autosomal recessive (AR) diseases and uniparental disomy (UPD). Results of genetic testing among pediatric patients from 2015 to 2019 were evaluated. Diagnostic findings with detected ROH from large consecutive case series in the literature were reviewed. Of 2050 pediatric patients, 65 (3%) had one or more ROH and 31 (53%) had follow-up whole exome sequencing (WES) and methylation studies. Seven homozygous variants were detected and four of them from three patients (9.6%) were within the detected ROH and classified as pathogenic or likely pathogenic variants for AR diseases. One patient (3%) had segmental UPD15q for a diagnosis of Prader-Willi syndrome. Additive diagnostic yield from ROH reporting was at least 0.2% (4/2050) of pediatric patients. These results were consistent with findings from several large case series reported in the literature. Detecting ROH had an estimated baseline predictive value of 10% for AR diseases and 3% for UPD. Consanguinity revealed by multiple ROH was a strong predictor for AR diseases. These results provide evidence for genetic counseling and recommendation of follow-up WES and methylation studies for pediatric patients reported with ROH.