Relationships between estimated autozygosity and complex traits in the UK Biobank

<div><p>Inbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts—stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. Care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits.</p></div

Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation

We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD

Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease

Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity

Analysis of gene conversion tracts in \u3ci\u3eSaccharomyces cerevisiae\u3c/i\u3e

Common fragile sites are regions of the genome prone to gaps and breakage under replication stress. Repair of breaks at CFS can occur through homologous recombination. yet may lead to loss of heterozygosity (LOH) events that manifest themselves as gene conversions. Gene conversions associated with LOH have the potential to deactivate tumor suppressor genes, driving tumor progression. Using the yeast model, Saccharomyces cerevisiae, evidence of two types of gene conversions has emerged: short-tract and long-tract gene conversions. Gene conversion maps show a high frequency of short-tract gene conversions ending near or at the SUP4-o tRNA, in yeast strain Y657 that contains SUP4-o. We hypothesized that termination of these tracts is due to replication fork pause sites created by SUP4-o. We find the 2% difference in frequency of terminations between Y657, and our experimental yeast strain that contains SUP4-o, AMC355, does not provide statistical support for our hypothesis of SUP4-o causing termination of gene conversion tracts. We see that gene conversions near SUP4-o vary in their tract length. These gene conversions have implications for possible LOH after repair at fragile sites and may contribute to cancer progression

Runs of homozygosity in killer whale genomes provide a global record of demographic histories

Runs of homozygosity (ROH) occur when offspring inherit haplotypes that are identical by descent from each parent. Length distributions of ROH are informative about population history; specifically, the probability of inbreeding mediated by mating system and/or population demography. Here, we investigated whether variation in killer whale (Orcinus orca) demographic history is reflected in genome-wide heterozygosity and ROH length distributions, using a global data set of 26 genomes representative of geographic and ecotypic variation in this species, and two F1 admixed individuals with Pacific-Atlantic parentage. We first reconstructed demographic history for each population as changes in effective population size through time using the pairwise sequential Markovian coalescent (PSMC) method. We found a subset of populations declined in effective population size during the Late Pleistocene, while others had more stable demography. Genomes inferred to have undergone ancestral declines in effective population size, were autozygous at hundreds of short ROH (1.5 Mb) were found in low latitude populations, and populations of known conservation concern. These include a Scottish killer whale, for which 37.8% of the autosomes were comprised of ROH >1.5 Mb in length. The fate of this population, in which only two adult males have been sighted in the past five years, and zero fecundity over the last two decades, may be inextricably linked to its demographic history and consequential inbreeding depression

Runs of homozygosity in killer whale genomes provide a global record of demographic histories

Runs of homozygosity (ROH) occur when offspring inherit haplotypes that are identical by descent from each parent. Length distributions of ROH are informative about population history; specifically, the probability of inbreeding mediated by mating system and/or population demography. Here, we investigated whether variation in killer whale (Orcinus orca) demographic history is reflected in genome-wide heterozygosity and ROH length distributions, using a global data set of 26 genomes representative of geographic and ecotypic variation in this species, and two F1 admixed individuals with Pacific-Atlantic parentage. We first reconstructed demographic history for each population as changes in effective population size through time using the pairwise sequential Markovian coalescent (PSMC) method. We found a subset of populations declined in effective population size during the Late Pleistocene, while others had more stable demography. Genomes inferred to have undergone ancestral declines in effective population size, were autozygous at hundreds of short ROH (\u3c1 \u3eMb), reflecting high background relatedness due to coalescence of haplotypes deep within the pedigree. In contrast, longer and therefore younger ROH (\u3e1.5 Mb) were found in low latitude populations, and populations of known conservation concern. These include a Scottish killer whale, for which 37.8% of the autosomes were comprised of ROH \u3e1.5 Mb in length. The fate of this population, in which only two adult males have been sighted in the past five years, and zero fecundity over the last two decades, may be inextricably linked to its demographic history and consequential inbreeding depression

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination

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

peer-reviewedRuns 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.Cino Pertoldi was supported by a grant from Danish Natural Science Research Council (Grant nos. 11-103926, 09-065999, and 95095995), the Carlsberg Foundation (Grant no. 2011- 01-0059), and the Aalborg Zoo Conservation Foundation (AZCF). Laura Iacolina has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Action (Grant Agreement no. 656697). Astrid V. Stronen received funding from the Danish Natural Science Research Council (Postdoctoral Grant 1337-00007)

Investigations of a novel retinal disease in Wiltshire sheep : a thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Studies in Veterinary Pathology at Massey University, Palmerston North, New Zealand

In 2011 and 2012, nine cases of adult-onset blindness were identified in a single flock of Wiltshire sheep. Affected sheep typically developed detectable night blindness at 2 to 3 years of age, which progressed to complete blindness by 4 to 5 years of age. Opthalmoscopically, the disease was characterised by progressive tapetal hyperreflectivity and attenuation of retinal blood vessels, indicative of retinal thinning and atrophy. Retinal histology revealed a selective loss of rod photoreceptors in the early stages of the disease, with preservation of cone photoreceptors. Secondary loss of cone photoreceptors was seen later in the course of the disease. Retinal degeneration was not accompanied by any other ocular or central nervous system abnormalities. Progressive retinal degeneration targeting rod photoreceptors has not been previously reported in sheep, but this disease has several similarities to inherited retinal dystrophies in other species, particularly progressive retinal atrophy in dogs and retinitis pigmentosa in humans. The disease in sheep is thought to be inherited in either an autosomal dominant or autosomal recessive manner, although additional cases identified recently provide further support for an autosomal dominant mode of inheritance. Initial investigations into the molecular basis of the disease, using a comparative candidate gene approach, did not identify any exonic single nucleotide polymorphisms (SNPs) in the rhodopsin gene of affected sheep that would alter the amino acid sequence. Homozygosity mapping of affected sheep revealed an identical-by-descent region on chromosome 5, but none of the genes within or surrounding this segment were considered to be plausible candidate genes except for GPR98, which is associated with retinitis pigmentosa and sensorineural hearing loss in humans. Investigations into the inheritance and molecular basis of this novel retinal degeneration in Wiltshire sheep are continuing, as this disease may prove to be a useful model for retinal dystrophies in other species, including retinitis pigmentosa in humans