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NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.

ABSTRACT: We herein report the result of a large-scale, next generation sequencing (NGS)-based screen for embryonic lethal (EL) mutations in Belgian beef and New Zealand dairy cattle. We estimated by simulation that cattle might carry, on average, ?0.5 recessive EL mutations. We mined exome sequence data from >600 animals, and identified 1377 stop-gain, 3139 frame-shift, 1341 splice-site, 22,939 disruptive missense, 62,399 benign missense, and 92,163 synonymous variants. We show that cattle have a comparable load of loss-of-function (LoF) variants (defined as stop-gain, frame-shift, or splice-site variants) as humans despite having a more variable exome. We genotyped >40,000 animals for up to 296 LoF and 3483 disruptive missense, breed-specific variants. We identified candidate EL mutations based on the observation of a significant depletion in homozygotes. We estimated the proportion of EL mutations at 15% of tested LoF and 6% of tested disruptive missense variants. We confirmed the EL nature of nine candidate variants by genotyping 200 carrier × carrier trios, and demonstrating the absence of homozygous offspring. The nine identified EL mutations segregate at frequencies ranging from 1.2% to 6.6% in the studied populations and collectively account for the mortality of ?0.6% of conceptuses. We show that EL mutations preferentially affect gene products fulfilling basic cellular functions. The resulting information will be useful to avoid at-risk matings, thereby improving fertility.

SUBMITTER: Charlier C

PROVIDER: S-EPMC5052051 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.

Charlier Carole C Li Wanbo W Harland Chad C Littlejohn Mathew M Coppieters Wouter W Creagh Frances F Davis Steve S Druet Tom T Faux Pierre P Guillaume François F Karim Latifa L Keehan Mike M Kadri Naveen Kumar NK Tamma Nico N Spelman Richard R Georges Michel M

Genome research 20160919 10

We herein report the result of a large-scale, next generation sequencing (NGS)-based screen for embryonic lethal (EL) mutations in Belgian beef and New Zealand dairy cattle. We estimated by simulation that cattle might carry, on average, ∼0.5 recessive EL mutations. We mined exome sequence data from >600 animals, and identified 1377 stop-gain, 3139 frame-shift, 1341 splice-site, 22,939 disruptive missense, 62,399 benign missense, and 92,163 synonymous variants. We show that cattle have a compara ...[more]

PMID: 27646536

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Project description:BackgroundHomozygous recessive deleterious mutations can cause embryo/fetal or neonatal lethality, or genetic defects that affect female fertility and animal welfare. In livestock populations under selection, the frequency of such lethal mutations may increase due to inbreeding, genetic drift, and/or the positive pleiotropic effects of heterozygous carriers on selected traits.ResultsBy scanning the genome of 19,102 Lacaune sheep using 50 k single nucleotide polymorphism (SNP) phased genotypes and pedigree data, we identified 11 Lacaune deficient homozygous haplotypes (LDHH1 to LDHH11) showing a highly significant deficit of homozygous animals ranging from 79 to 100%. These haplotypes located on chromosomes 3, 4, 13, 17 and 18, spanned regions from 1.2 to 3.0 Mb long with a frequency of heterozygous carriers between 3.7 and 12.1%. When we compared at-risk matings (between carrier rams and daughters of carrier rams) and safe matings, seven of the 11 haplotypes were associated with a significant alteration of two fertility traits, a reduced success of artificial insemination (LDHH1, 2, 8 and 9), and/or an increased stillbirth rate (LDHH3, 6, 8, 9, and 10). The 11 haplotypes were also tested for a putative selective advantage of heterozygous carrier rams based on their daughter yield deviation for six dairy traits (milk, fat and protein yields, fat and protein contents and lactation somatic cell score). LDHH1, 3, 4, 5, 7, 9 and 11 were associated with positive effects on at least one selected dairy trait, in particular milk yield. For each haplotype, the most probable candidate genes were identified based on their roles in lethality of mouse knock-out models and in mammalian genetic disorders.ConclusionsBased on a reverse genetic strategy, we identified at least 11 haplotypes with homozygous deficiency segregating in French Lacaune dairy sheep. This strategy represents a first tool to limit at-risk matings in the Lacaune dairy selection scheme. We assume that most of the identified LDHH are in strong linkage disequilibrium with a recessive lethal mutation that affects embryonic or juvenile survival in sheep but is yet to be identified.

Project description:The livestock industry in Mongolia accounts for 24% of national revenue, with one third of the population maintaining a pastoral lifestyle. This close connection between Mongolian population and livestock is a major concern for pathogen transfer, especially given the increase in vector-borne diseases globally. This study examines blood samples from livestock to assess the prevalence of tick-borne bacterial infections across three provinces in Mongolia (Dornogovi, Selenge, Töv). Whole blood samples from 243 livestock (cattle=38, camel=11, goat=85, horse=22, sheep=87) were analyzed with 16S metagenomics next-generation sequencing (NGS) to screen for bacterial pathogens. Positive-NGS samples for Anaplasma, Bartonella, Ehrlichia, Francisella, Leptospira, and Rickettsia were confirmed by conventional PCR and DNA sequencing. Prevalence rates of Anaplasma, Bartonella, and Ehrlichia were 57.6%, 12.8%, and 0.4%, respectively. A significant difference in the prevalence of Anaplasma spp. in livestock by province was observed, with a higher prevalence in Selenge (74.2%, p<0.001) and Töv (64.2% p = 0.006) compared to the semi-arid region of Dornogovi (39.8%). In contrast, no association was observed in Bartonella prevalence by provinces. All Anaplasma sequences (N = 139) were characterized as A. ovis. For Bartonella species characterization, phylogenetic analyses of gltA and rpoB genes identified three Bartonella species including B. bovis, B. melophagi and Candidatus B. ovis. Bartonella bovis was detected in all 22-positive cattle, while B. melophagi and Candidatus B. ovis were found in four and three sheep, respectively. This study identifies a high prevalence of tick-borne pathogens within the livestock population and to our knowledge, is the first time NGS methods have been used to explore tick-borne diseases in Mongolia. Further research is needed in Mongolia to better understand the clinical and economic burdens associated with tick-borne diseases in both livestock and pastoral herder populations.

Dataset Information

NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.

Publications

NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.

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