Number Of Runs Of Homozygosity Research Articles

Genomic evaluation of resistance to Haemonchus contortus in a South African Dohne Merino flock

The aim of this study was to use genome-wide SNP data to investigate phenotypic and genetic differences in resistance to Haemonchus contortus between resistant and susceptible South African Dohne Merino sheep. The participating farm (Wauldby) has a history of heavy H. contortus challenge and implemented a selection strategy for resistance to H. contortus in 2011. Faecal egg count (FEC), body condition scores (BCS) and Famacha© scores (FAM) were recorded annually on lambs from weaning in January until the end of June from 2011 to 2014. Animals with FAM scores of ≥ 2.5 or BCS scores < 1.5 were subjected to anthelmintic treatment and recorded as “Dosed” animals. Animals (196) were selected for genotyping based on EBV for FEC and classified into Case and Control groups on the basis of whether they were dosed or not. The Grootfontein Dohne Merino flock has never been subjected to selection for resistance to gastrointestinal parasites and 48 animals were selected on FEC for genotyping. DNA obtained from blood samples were genotyped using the Illumina® Ovine SNP50 BeadChip. Principal component analysis (PCA) resulted in four distinct genetic clusters, with the Grootfontein sheep population clustering separately. The Wauldby animals in Cluster 3 had significantly lower FEC and higher BCS than the animals in Clusters 2 and 4. FEC breeding values of 114 ± 97, -629 ± 84 and -2 ± 45 were recorded for PCA-based Genetic cluster 2, 3 and 4 animals, respectively. The majority (88%) of animals in Cluster 3 were the progeny of sires from the resistant line. The average number of runs of homozygosity (ROH) was 44, 46, 54 and 47 per animal for Clusters 1, 2, 3 and 4 respectively. The highest number of ROHs was found on chromosomes 1, 2, 3, 4, 6, 9 and 10, on which QTL for resistance traits have been identified previously. Sires in Genetic cluster 3 were highly resistant and can be used in a breeding program to develop H. contortus resistant sheep. The results indicated genetic variation in host resistance against H. contortus in the Wauldby flock and breeding for resistance against nematodes is feasible.

Selection signatures in four German warmblood horse breeds: Tracing breeding history in the modern sport horse.

The study of selection signatures helps to find genomic regions that have been under selective pressure and might host genes or variants that modulate important phenotypes. Such knowledge improves our understanding of how breeding programmes have shaped the genomes of livestock. In this study, 942 stallions were included from four, exemplarily chosen, German warmblood breeds with divergent historical and recent selection focus and different crossbreeding policies: Trakehner (N = 44), Holsteiner (N = 358), Hanoverian (N = 319) and Oldenburger (N = 221). Those breeds are nowadays bred for athletic performance and aptitude for show-jumping, dressage or eventing, with a particular focus of Holsteiner on the first discipline. Blood samples were collected during the health exams of the stallion preselections before licensing and were genotyped with the Illumina EquineSNP50 BeadChip. Autosomal markers were used for a multi-method search for signals of positive selection. Analyses within and across breeds were conducted by using the integrated Haplotype Score (iHS), cross-population Extended Haplotype Homozygosity (xpEHH) and Runs of Homozygosity (ROH). Oldenburger and Hanoverian showed very similar iHS signatures, but breed specificities were detected on multiple chromosomes with the xpEHH. The Trakehner clustered as a distinct group in a principal component analysis and also showed the highest number of ROHs, which reflects their historical bottleneck. Beside breed specific differences, we found shared selection signals in an across breed iHS analysis on chromosomes 1, 4 and 7. After investigation of these iHS signals and shared ROH for potential functional candidate genes and affected pathways including enrichment analyses, we suggest that genes affecting muscle functionality (TPM1, TMOD2-3, MYO5A, MYO5C), energy metabolism and growth (AEBP1, RALGAPA2, IGFBP1, IGFBP3-4), embryonic development (HOXB-complex) and fertility (THEGL, ZPBP1-2, TEX14, ZP1, SUN3 and CFAP61) have been targeted by selection in all breeds. Our findings also indicate selection pressure on KITLG, which is well-documented for influencing pigmentation.

Genome-wide patterns of homozygosity provide clues about the population history and adaptation of goats

BackgroundPatterns of homozygosity can be influenced by several factors, such as demography, recombination, and selection. Using the goat SNP50 BeadChip, we genotyped 3171 goats belonging to 117 populations with a worldwide distribution. Our objectives were to characterize the number and length of runs of homozygosity (ROH) and to detect ROH hotspots in order to gain new insights into the consequences of neutral and selection processes on the genome-wide homozygosity patterns of goats.ResultsThe proportion of the goat genome covered by ROH is, in general, less than 15% with an inverse relationship between ROH length and frequency i.e. short ROH (< 3 Mb) are the most frequent ones. Our data also indicate that ~ 60% of the breeds display low FROH coefficients (< 0.10), while ~ 30 and ~ 10% of the goat populations show moderate (0.10 < FROH < 0.20) or high (> 0.20) FROH values. For populations from Asia, the average number of ROH is smaller and their coverage is lower in goats from the Near East than in goats from Central Asia, which is consistent with the role of the Fertile Crescent as the primary centre of goat domestication. We also observed that local breeds with small population sizes tend to have a larger fraction of the genome covered by ROH compared to breeds with tens or hundreds of thousands of individuals. Five regions on three goat chromosomes i.e. 11, 12 and 18, contain ROH hotspots that overlap with signatures of selection.ConclusionsPatterns of homozygosity (average number of ROH of 77 and genome coverage of 248 Mb; FROH < 0.15) are similar in goats from different geographic areas. The increased homozygosity in local breeds is the consequence of their small population size and geographic isolation as well as of founder effects and recent inbreeding. The existence of three ROH hotspots that co-localize with signatures of selection demonstrates that selection has also played an important role in increasing the homozygosity of specific regions in the goat genome. Finally, most of the goat breeds analysed in this work display low levels of homozygosity, which is favourable for their genetic management and viability.

Inbreeding depression in line 1 Hereford cattle population using pedigree and genomic information.

This study aimed at assessing inbreeding and its effect on growth and fertility traits using the longtime closed line 1 Hereford cattle population. Inbreeding was estimated based on pedigree (FPED) and genomic information. For the latter, three estimates were derived based on the diagonal elements of the genomic relationship matrix using estimated (FGRM) or fixed (FGRM0.5) minor allele frequencies or runs of homozygosity (ROH) (FROH). A pedigree containing 10,186 animals was used to calculate FPED. Genomic inbreeding was evaluated using 785 animals genotyped for 30,810 SNP. Traits analyzed were birth weight (BWT), weaning weight (WWT), yearling weight (YWT), ADG, and age at first calving (AFC). The number of ROH per animal ranged between 6 and 119 segments with an average of 83. The shortest and longest segments were 1.36 and 64.86 Mb long, respectively, reflecting both ancient and recent inbreeding occurring in the last 30 to 40 generations. The average inbreeding was 29.2%, 16.1%, 30.2%, and 22.9% for FPED, FGRM, FGRM0.5, and FROH, respectively. FROH provided the highest correlations with FPED (r = 0.66). Across paternal half-sib families, with minimal variation in FPED, there were substantial variations in their genomic inbreeding. Inbreeding depression analyses showed that a 1% increase in an animal's FPED resulted in a decrease of 1.20 kg, 2.03 kg, and 0.004 kg/d in WWT, YWT, and ADG, respectively. Maternal inbreeding showed significantly negative effects on progeny growth performance. AFC increased by 1.4 and 0.8 d for each 1% increase in FPED of the cow and her dam, respectively. Using genomic inbreeding, similar impact on growth traits was observed although the magnitude of the effect varied between methods. Across all genomic measures, WWT, YWT, and ADG decreased by 0.21 to 0.53 kg, 0.46 to 1.13 kg, and 0.002 to 0.006 kg/d for each 1% increase in genomic inbreeding, respectively. Four chromosomes (9, 12, 17, and 27) were identified to have a significant association between their homozygosity (FROH-CHR) and growth traits. Variability in genomic inbreeding could be useful when deciding between full and half-sib selection candidates. Despite the high level of inbreeding in this study, its negative impact on growth performance was not as severe as expected, which may be attributed to the purging of the deleterious alleles due to natural or artificial selection over time.

Runs of Homozygosity and Population History of Three Horse Breeds With Small Population Size

Long consecutive homozygous genotype segments, runs of homozygosity (ROH), are a result of parents transmitting identical haplotypes, which can be used to estimate autozygosity. Based on 612K single-nucleotide polymorphisms, we computed three ROH parameters (genome length covered by ROH, SROH; number of ROH, NROH; and autozygosity, FROH) to investigate different scenarios in contemporary horse breeding: limited census (Bosnian mountain horse), conservation breeding (Posavje horse), and selection within closed studbook (Haflinger). The ROH parameters revealed well-defined differences between breeds. SROH was highest in the Bosnian mountain horse with 296.32 Mb, followed by the Haflinger sample (SROH = 270.35 Mb) and the Posavje sample with 192.68 Mb. The highest number of ROH segments (ROHs) was observed within the Haflinger sample followed by the Posavje sample. FROH ranged at a population level from 8.59% in Posavje, over the Haflinger (mean FROH = 12.05%) to 13.21% in the Bosnian mountain horse breed. Bottlenecks were detected for Bosnian mountain horse and Haflinger, whereas for the Posavje, a positive effect of the conservation breeding program was documented. Investigating the distribution of ROHs across the genome, we detected four common ROH islands on equine chromosomes ECA 6, ECA 11, and ECA 17, which were present in all breeds. On breed level, the Bosnian mountain horses contained 10, the Posavje, four, and the Haflinger, 11 distinct ROH islands (containing the MC1R locus on ECA 3). With this analysis, we were able to compare genomic levels of inbreeding between breeds differing in management, pedigree completeness, and genes under selection.

Runs of homozygosity in a selected cattle population with extremely inbred bulls: Descriptive and functional analyses revealed highly variable patterns.

The analysis of runs of homozygosity (ROH), using high throughput genomic data, has become a valuable and frequently used methodology to characterize the genomic and inbreeding variation of livestock and wildlife animal populations. However, this methodology has been scarcely used in highly inbred domestic animals. Here, we analyzed and characterized the occurrence of ROH fragments in highly inbred (HI; average pedigree-based inbreeding coefficient FPED = 0.164; 0.103 to 0.306) and outbred Retinta bulls (LI; average FPED = 0.008; 0 to 0.025). We studied the length of the fragments, their abundance, and genome distribution using high-density microarray data. The number of ROH was significantly higher in the HI group, especially for long fragments (>8Mb). In the LI group, the number of ROH continuously decreased with fragment length. Genome-wide distribution of ROH was highly variable between samples. Some chromosomes presented a larger number of fragments (BTA1, BTA19, BTA29), others had longer fragments (BTA4, BTA12, BTA17), while other ones showed an increased ROH accumulation over specific loci (BTA2, BTA7, BTA23, BTA29). Similar differences were observed in the analysis of 12 individuals produced by a similar inbred event (FPED3 = 0.125). The correlation between the fraction of the genome covered by ROH (FROH) and FPED was high (0.79), suggesting that ROH-based estimations are indicative of inbreeding levels. On the other hand, the correlation between FPED and the microsatellite-based inbreeding coefficient (FMIC) was only moderate (r = 0.44), suggesting that STR-based inbreeding estimations should be avoided. Similarly, we found a very low correlation (r = -0.0132) between recombination rate and ROH abundance across the genome. Finally, we performed functional annotation analyses of genome regions with significantly enriched ROH abundance. Results revealed gene clusters related to pregnancy-associated proteins and immune reaction. The same analysis performed for regions enriched with recently formed ROH (> 8 Mb) showed gene clusters related to flagellum assembly. In both cases, the processes were related to male and female reproductive functions, which may partially explain the reduced fertility associated with inbred populations.

Inbreeding and runs of homozygosity before and after genomic selection in North American Holstein cattle

BackgroundWhile autozygosity as a consequence of selection is well understood, there is limited information on the ability of different methods to measure true inbreeding. In the present study, a gene dropping simulation was performed and inbreeding estimates based on runs of homozygosity (ROH), pedigree, and the genomic relationship matrix were compared to true inbreeding. Inbreeding based on ROH was estimated using SNP1101, PLINK, and BCFtools software with different threshold parameters. The effects of different selection methods on ROH patterns were also compared. Furthermore, inbreeding coefficients were estimated in a sample of genotyped North American Holstein animals born from 1990 to 2016 using 50 k chip data and ROH patterns were assessed before and after genomic selection.ResultsUsing ROH with a minimum window size of 20 to 50 using SNP1101 provided the closest estimates to true inbreeding in simulation study. Pedigree inbreeding tended to underestimate true inbreeding, and results for genomic inbreeding varied depending on assumptions about base allele frequencies. Using an ROH approach also made it possible to assess the effect of population structure and selection on distribution of runs of autozygosity across the genome. In the simulation, the longest individual ROH and the largest average length of ROH were observed when selection was based on best linear unbiased prediction (BLUP), whereas genomic selection showed the largest number of small ROH compared to BLUP estimated breeding values (BLUP-EBV). In North American Holsteins, the average number of ROH segments of 1 Mb or more per individual increased from 57 in 1990 to 82 in 2016. The rate of increase in the last 5 years was almost double that of previous 5 year periods. Genomic selection results in less autozygosity per generation, but more per year given the reduced generation interval.ConclusionsThis study shows that existing software based on the measurement of ROH can accurately identify autozygosity across the genome, provided appropriate threshold parameters are used. Our results show how different selection strategies affect the distribution of ROH, and how the distribution of ROH has changed in the North American dairy cattle population over the last 25 years.

Genome-wide scan for runs of homozygosity identifies potential candidate genes associated with local adaptation in Valle del Belice sheep

BackgroundBecause very large numbers of single nucleotide polymorphisms (SNPs) are now available throughout the genome, they are particularly suitable for the detection of genomic regions where a reduction in heterozygosity has occurred and they offer new opportunities to improve the accuracy of inbreeding (F) estimates. Runs of homozygosity (ROH) are contiguous lengths of homozygous segments of the genome where the two haplotypes inherited from the parents are identical. Here, we investigated the occurrence and distribution of ROH using a medium-dense SNP panel to characterize autozygosity in 516 Valle del Belice sheep and to identify the genomic regions with high ROH frequencies.ResultsWe identified 11,629 ROH and all individuals displayed at least one ROH longer than 1 Mb. The mean value of F estimated from ROH longer than1 Mb was 0.084 ± 0.061. ROH that were shorter than 10 Mb predominated. The highest and lowest coverages of Ovis aries chromosomes (OAR) by ROH were on OAR24 and OAR1, respectively. The number of ROH per chromosome length displayed a specific pattern, with higher values for the first three chromosomes. Both number of ROH and length of the genome covered by ROH varied considerably between animals. Two hundred and thirty-nine SNPs were considered as candidate markers that may be under directional selection and we identified 107 potential candidate genes. Six genomic regions located on six chromosomes, corresponding to ROH islands, are presented as hotspots of autozygosity, which frequently coincided with regions of medium recombination rate. According to the KEGG database, most of these genes were involved in multiple signaling and signal transduction pathways in a wide variety of cellular and biochemical processes. A genome scan revealed the presence of ROH islands in genomic regions that harbor candidate genes for selection in response to environmental stress and which underlie local adaptation.ConclusionsThese results suggest that natural selection has, at least partially, a role in shaping the genome of Valle del Belice sheep and that ROH in the ovine genome may help to detect genomic regions involved in the determinism of traits under selection.

P4060 Runs of homozygosity reveal natural selection footprints of some African chicken breeds and village ecotypes

The earliest evidence of domestic chicken (Gallus gallus) introduction into Africa was in Egypt in the New Kingdom, 19th Dynasty (1307–1196 BC) through the ancient cinnamon trade. Chickens were introduced in Eastern Africa (EA) later via Egypt or direct introduction via Indian Ocean trading. With the absence of genetic improvement schemes and breeding associations, EA rural chicken populations are likely under natural selection, and most are considered as ecotypes, not breeds. A few populations, e.g., Egyptian Fayoumi have fixed criteria and are registered as a breed. The current study aims to assess probable co-ancestry among six African chicken populations, in comparison with a highly inbred US Fayoumi line, to investigate the inter-population genomic variation due to natural selective pressure and to determine functional variants associated with Runs of Homozygosity (ROH). The populations studied included three indigenous African ecotypes from Uganda (UGN), Rwanda (RWN) and Egyptian naked-neck (ENN); two Egyptian registered breeds; Fayoumi (FEG) and Dandarawi (DEG), one hybrid developed in India and sampled in Uganda, Kuroiler (KRL), and a highly inbred US Fayoumi (FUS). A total of 290 birds were randomly sampled from villagers in Egypt, Rwanda, and Uganda, representing indigenous populations, and 6 birds were sampled from the inbred FUS flock. Birds were genotyped using the Affymetrix 600K Axiom® Genome-Wide Chicken Genotyping Array. ROH were defined using PLINK v1.9, for a minimum ROH length of 500kb, with no more than one missing SNP and one heterozygous SNP genotype per window. A total number of 15,277 ROH were detected across the studied populations. ROH length ranged between 500kb to around 50Mb. ROH were classified into three length categories; short (500kb to < 1Mb, n = 9970; 65.3%); medium (1Mb to < 5Mb, n = 4960; 32.5%) and long (≥ 5Mb, n = 347; 2.3%). The average number of ROH per bird was highest for the inbred FUS (240.7), and the least for the DAN (19.9) indicating outbreeding. Intra-breed regions with a high occurrence of ROH were identified on several chromosomes indicating ROH landscaping, where several genes involved in survivability and tolerance (i.e., reproduction, metabolism, muscle formation, ion-exchange, and heat and oxidative stresses tolerance) were detected. This study illustrates the distribution of ROH and functional variants within ROH in some African breeds and ecotypes. Detecting genomic regions involved in traits under natural selection contributes to our understanding of regions of importance for selection and distribution of functional variants in the chicken genome.

Novel Graphical Analyses of Runs of Homozygosity among Species and Livestock Breeds.

Runs of homozygosity (ROH), uninterrupted stretches of homozygous genotypes resulting from parents transmitting identical haplotypes to their offspring, have emerged as informative genome-wide estimates of autozygosity (inbreeding). We used genomic profiles based on 698 K single nucleotide polymorphisms (SNPs) from nine breeds of domestic cattle (Bos taurus) and the European bison (Bison bonasus) to investigate how ROH distributions can be compared within and among species. We focused on two length classes: 0.5–15 Mb to investigate ancient events and >15 Mb to address recent events (approximately three generations). For each length class, we chose a few chromosomes with a high number of ROH, calculated the percentage of times a SNP appeared in a ROH, and plotted the results. We selected areas with distinct patterns including regions where (1) all groups revealed an increase or decrease of ROH, (2) bison differed from cattle, (3) one cattle breed or groups of breeds differed (e.g., dairy versus meat cattle). Examination of these regions in the cattle genome showed genes potentially important for natural and human-induced selection, concerning, for example, meat and milk quality, metabolism, growth, and immune function. The comparative methodology presented here permits visual identification of regions of interest for selection, breeding programs, and conservation.

Genomic inbreeding estimation in small populations: evaluation of runs of homozygosity in three local dairy cattle breeds

In the local breeds with small population size, one of the most important problems is the increase of inbreeding coefficient (F). High levels of inbreeding lead to reduced genetic diversity and inbreeding depression. The availability of high-density single nucleotide polymorphism (SNP) arrays has facilitated the quantification of F by genomic markers in farm animals. Runs of homozygosity (ROH) are contiguous lengths of homozygous genotypes and represent an estimate of the degree of autozygosity at genome-wide level. The current study aims to quantify the genomic F derived from ROH (FROH) in three local dairy cattle breeds. FROH values were compared with F estimated from the genomic relationship matrix (FGRM), based on the difference between observed v. expected number of homozygous genotypes (FHOM) and the genomic homozygosity of individual i (FMOL i). The molecular coancestry coefficient (fMOL ij) between individuals i and j was also estimated. Individuals of Cinisara (71), Modicana (72) and Reggiana (168) were genotyped with the 50K v2 Illumina BeadChip. Genotypes from 96 animals of Italian Holstein cattle breed were also included in the analysis. We used a definition of ROH as tracts of homozygous genotypes that were >4 Mb. Among breeds, 3661 ROH were identified. Modicana showed the highest mean number of ROH per individual and the highest value of FROH, whereas Reggiana showed the lowest ones. Differences among breeds existed for the ROH lengths. The individuals of Italian Holstein showed high number of short ROH segments, related to ancient consanguinity. Similar results showed the Reggiana with some extreme animals with segments covering 400 Mb and more of genome. Modicana and Cinisara showed similar results between them with the total length of ROH characterized by the presence of large segments. High correlation was found between FHOM and FROH ranged from 0.83 in Reggiana to 0.95 in Cinisara and Modicana. The correlations among FROH and other estimated F coefficients were generally lower ranged from 0.45 (FMOL i−FROH) in Cinisara to 0.17 (FGRM−FROH) in Modicana. On the basis of our results, recent inbreeding was observed in local breeds, considering that 16 Mb segments are expected to present inbreeding up to three generations ago. Our results showed the necessity of implementing conservation programs to control the rise of inbreeding and coancestry in the three Italian local dairy cattle breeds.

Inbreeding and homozygosity in breast cancer survival.

Genome-wide association studies (GWASs) help to understand the effects of single nucleotide polymorphisms (SNPs) on breast cancer (BC) progression and survival. We performed multiple analyses on data from a previously conducted GWAS for the influence of individual SNPs, runs of homozygosity (ROHs) and inbreeding on BC survival. (I.) The association of individual SNPs indicated no differences in the proportions of homozygous individuals among short-time survivors (STSs) and long-time survivors (LTSs). (II.) The analysis revealed differences among the populations for the number of ROHs per person and the total and average length of ROHs per person and among LTSs and STSs for the number of ROHs per person. (III.) Common ROHs at particular genomic positions were nominally more frequent among LTSs than in STSs. Common ROHs showed significant evidence for natural selection (iHS, Tajima’s D, Fay-Wu’s H). Most regions could be linked to genes related to BC progression or treatment. (IV.) Results were supported by a higher level of inbreeding among LTSs. Our results showed that an increased level of homozygosity may result in a preference of individuals during BC treatment. Although common ROHs were short, variants within ROHs might favor survival of BC and may function in a recessive manner.

Runs of homozygosity reveal signatures of positive selection for reproduction traits in breed and non-breed horses.

BackgroundModern horses represent heterogeneous populations specifically selected for appearance and performance. Genomic regions under high selective pressure show characteristic runs of homozygosity (ROH) which represent a low genetic diversity. This study aims at detecting the number and functional distribution of ROHs in different horse populations using next generation sequencing data.MethodsNext generation sequencing was performed for two Sorraia, one Dülmen Horse, one Arabian, one Saxon-Thuringian Heavy Warmblood, one Thoroughbred and four Hanoverian. After quality control reads were mapped to the reference genome EquCab2.70. ROH detection was performed using PLINK, version 1.07 for a trimmed dataset with 11,325,777 SNPs and a mean read depth of 12. Stretches with homozygous genotypes of >40 kb as well as >400 kb were defined as ROHs. SNPs within consensus ROHs were tested for neutrality. Functional classification was done for genes annotated within ROHs using PANTHER gene list analysis and functional variants were tested for their distribution among breed or non-breed groups.ResultsROH detection was performed using whole genome sequences of ten horses of six populations representing various breed types and non-breed horses. In total, an average number of 3492 ROHs were detected in windows of a minimum of 50 consecutive homozygous SNPs and an average number of 292 ROHs in windows of 500 consecutive homozygous SNPs. Functional analyses of private ROHs in each horse revealed a high frequency of genes affecting cellular, metabolic, developmental, immune system and reproduction processes. In non-breed horses, 198 ROHs in 50-SNP windows and seven ROHs in 500-SNP windows showed an enrichment of genes involved in reproduction, embryonic development, energy metabolism, muscle and cardiac development whereas all seven breed horses revealed only three common ROHs in 50-SNP windows harboring the fertility-related gene YES1. In the Hanoverian, a total of 18 private ROHs could be shown to be located in the region of genes potentially involved in neurologic control, signaling, glycogen balance and reproduction. Comparative analysis of homozygous stretches common in all ten horses displayed three ROHs which were all located in the region of KITLG, the ligand of KIT known to be involved in melanogenesis, haematopoiesis and gametogenesis.ConclusionsThe results of this study give a comprehensive insight into the frequency and number of ROHs in various horses and their potential influence on population diversity and selection pressures. Comparisons of breed and non-breed horses suggest a significant artificial as well as natural selection pressure on reproduction performance in all types of horse populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1977-3) contains supplementary material, which is available to authorized users.

Estimation of Recent and Ancient Inbreeding in a Small Endogamous Tunisian Community Through Genomic Runs of Homozygosity.

Runs of homozygosity (ROHs) are extended genomic regions of homozygous genotypes that record populations' mating patterns in the past. We performed microarray genotyping on 15 individuals from a small isolated Tunisian community. We estimated the individual and population genome-wide level of homozygosity from data on ROH above 0.5 Mb in length. We found a high average number of ROH per individual (48.2). The smallest ROH category (0.5-1.49 Mb) represents 0.93% of the whole genome, while medium-size (1.5-4.99 Mb) and long-size ROH (≥5 Mb) cover 1.18% and 0.95%, respectively. We found that genealogical individual inbreeding coefficients (Fped ) based on three- to four-generation pedigrees are not reliable indicators of the current proportion of genome-wide homozygosity inferred from ROH (FROH ) either for 0.5 or 1.5 Mb ROH length thresholds, while identity-by-descent sharing is a function of shared coancestry. This study emphasizes the effect of reproductive isolation and a prolonged practice of consanguinity that limits the genetic heterogeneity. It also provides evidence of both recent and ancient parental relatedness contribution to the current level of genome-wide homozygosity in the studied population. These findings may be useful for evaluation of long-term effects of inbreeding on human health and for future applications of ROHs in identifying recessive susceptibility genes.

Analysis of runs of homozygosity and their relationship with inbreeding in five cattle breeds farmed in Italy.

Increased inbreeding is an inevitable consequence of selection in livestock populations. The analysis of high-density single nucleotide polymorphisms (SNPs) facilitates the identification of long and uninterrupted runs of homozygosity (ROH) that can be used to identify chromosomal regions that are identical by descent. In this work, the distribution of ROH of different lengths in five Italian cattle breeds is described. A total of 4095 bulls from five cattle breeds (2093 Italian Holstein, 749 Italian Brown, 364 Piedmontese, 410 Marchigiana and 479 Italian Simmental) were genotyped at 54K SNP loci. ROH were identified and used to estimate molecular inbreeding coefficients (FROH ), which were compared with inbreeding coefficients estimated from pedigree information (FPED ) and using the genomic relationship matrix (FGRM ). The average number of ROH per animal ranged from 54 ± 7.2 in Piedmontese to 94.6 ± 11.6 in Italian Brown. The highest number of short ROH (related to ancient consanguinity) was found in Piedmontese, followed by Simmental. The Italian Brown and Holstein had a higher proportion of longer ROH distributed across the whole genome, revealing recent inbreeding. The FPED were moderately correlated with FROH > 1 Mb (0.662, 0.700 and 0.669 in Italian Brown, Italian Holstein and Italian Simmental respectively) but poorly correlated with FGRM (0.134, 0.128 and 0.448 for Italian Brown, Italian Holstein and Italian Simmental respectively). The inclusion of ROH > 8 Mb in the inbreeding calculation improved the correlation of FROH with FPED and FGRM . ROH are a direct measure of autozygosity at the DNA level and can overcome approximations and errors resulting from incomplete pedigree data. In populations with high linkage disequilibrium (LD) and recent inbreeding (e.g. Italian Holstein and Italian Brown), a medium-density marker panel, such as the one used here, may provide a good estimate of inbreeding. However, in populations with low LD and ancient inbreeding, marker density would have to be increased to identify short ROH that are identical by descent more precisely.

High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis

Background: Large population-based genome-wide association studies have identified several multiple sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies. Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded conflicting results. Objectives: In this study we investigated the role of consanguinity on MS risk in the relatively isolated Faroe Islands, which have a presumed high level of inbreeding. Methods: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients, number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes as measures of relatedness. Parametric and non-parametric statistical models were applied. Results: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding coefficients, large number of observed homozygotes and many long ROH. However, apart from the number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed. Conclusions: Overall, no significant difference between cases and controls were found, indicating that consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe Islands.

Colorectal Cancer Risk Is Not Associated with Increased Levels of Homozygosity in a Population from the United Kingdom

Genome-wide association studies have identified several common single nucleotide polymorphisms (SNP) associated with an increased risk of colorectal cancer (CRC), although they have failed to identify any recessively acting alleles that contribute to disease risk. However, two recent studies have suggested that inbreeding and runs of homozygosity (ROH) increase the risk of developing cancer, perhaps by exposing recessive alleles as a result of autozygosity. To examine these results in a relatively large case-control series, we analyzed samples from a cohort in the United Kingdom comprising 921 colorectal tumor cases and 929 controls. Individuals were genotyped using a 550,000 tagging SNP panel. Additionally, we identified from these SNPs a set of approximately 30,000 SNPs in low pairwise linkage disequilibrium. To determine whether homozygosity was associated with CRC, we performed multiple tests to assess homozygosity at individual SNPs and ROHs in cases and controls. No association was found between CRC and (i) homozygosity at any individual SNP, (ii) overall homozygosity or level of inbreeding, (iii) total length or number of ROHs per individual, or (iv) a ROH at any particular genomic location. In conclusion, our results from a large case-control series do not replicate those of previous studies and suggest that homozygosity/autozygosity is not a major risk factor for CRC in an outbred population.

Runs of Homozygosity in European Populations

Estimating individual genome-wide autozygosity is important both in the identification of recessive disease variants via homozygosity mapping and in the investigation of the effects of genome-wide homozygosity on traits of biomedical importance. Approaches have tended to involve either single-point estimates or rather complex multipoint methods of inferring individual autozygosity, all on the basis of limited marker data. Now, with the availability of high-density genome scans, a multipoint, observational method of estimating individual autozygosity is possible. Using data from a 300,000 SNP panel in 2618 individuals from two isolated and two more-cosmopolitan populations of European origin, we explore the potential of estimating individual autozygosity from data on runs of homozygosity (ROHs). Termed F(roh), this is defined as the proportion of the autosomal genome in runs of homozygosity above a specified length. Mean F(roh) distinguishes clearly between subpopulations classified in terms of grandparental endogamy and population size. With the use of good pedigree data for one of the populations (Orkney), F(roh) was found to correlate strongly with the inbreeding coefficient estimated from pedigrees (r = 0.86). Using pedigrees to identify individuals with no shared maternal and paternal ancestors in five, and probably at least ten, generations, we show that ROHs measuring up to 4 Mb are common in demonstrably outbred individuals. Given the stochastic variation in ROH number, length, and location and the fact that ROHs are important whether ancient or recent in origin, approaches such as this will provide a more useful description of genomic autozygosity than has hitherto been possible.