So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Molecular dissection of a quantitative trait locus: a phenylalanine-to-tyrosine substitution in the transmembrane domain of the bovine growth hormone receptor is associated with a major effect on milk yield and composition.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

The Cancer Genome Atlas (TCGA) has accrued RNA-Seq-based transcriptome data for more than 4000 cancer tissue samples across 12 cancer types, translating these data into biological insights remains a major challenge. We analyzed and compared the transcriptomes of 4043 cancer and 548 normal tissue samples from 21 TCGA cancer types, and created a comprehensive catalog of gene expression alterations for each cancer type. By clustering genes into co-regulated gene sets, we identified seven cross-cancer gene signatures altered across a diverse panel of primary human cancer samples. A 14-gene signature extracted from these seven cross-cancer gene signatures precisely differentiated between cancerous and normal samples, the predictive accuracy of leave-one-out cross-validation (LOOCV) were 92.04%, 96.23%, 91.76%, 90.05%, 88.17%, 94.29%, and 99.10% for BLCA, BRCA, COAD, HNSC, LIHC, LUAD, and LUSC, respectively. A lung cancer-specific gene signature, containing SFTPA1 and SFTPA2 genes, accurately distinguished lung cancer from other cancer samples, the predictive accuracy of LOOCV for TCGA and GSE5364 data were 95.68% and 100%, respectively. These gene signatures provide rich insights into the transcriptional programs that trigger tumorigenesis and metastasis, and many genes in the signature gene panels may be of significant value to the diagnosis and treatment of cancer.

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Large-scale RNA-Seq Transcriptome Analysis of 4043 Cancers and 548 Normal Tissue Controls across 12 TCGA Cancer Types.

Pork quality is an economically important trait and one of the main selection criteria for breeding in the swine industry. In this genome-wide association study (GWAS), 455 pigs from a porcine Large White × Minzhu intercross population were genotyped using the Illumina PorcineSNP60K Beadchip, and phenotyped for intramuscular fat content (IMF), marbling, moisture, color L*, color a*, color b* and color score in the longissimus muscle (LM). Association tests between each trait and the SNPs were performed via the Genome Wide Rapid Association using the Mixed Model and Regression-Genomic Control (GRAMMAR-GC) approach. From the Ensembl porcine database, SNP annotation was implemented using Sus scrofa Build 9. A total of 45 SNPs showed significant association with one or multiple meat quality traits. Of the 45 SNPs, 36 were located on SSC12. These significantly associated SNPs aligned to or were in close approximation to previously reported quantitative trait loci (QTL) and some were located within introns of previously reported candidate genes. Two haplotype blocks ASGA0100525-ASGA0055225-ALGA0067099-MARC0004712-DIAS0000861, and ASGA0085522-H3GA0056170 were detected in the significant region. The first block contained the genes MYH1, MYH2 and MYH4. A SNP (ASGA0094812) within an intron of the USP43 gene was significantly associated with five meat quality traits. The present results effectively narrowed down the associated regions compared to previous QTL studies and revealed haplotypes and candidate genes on SSC12 for meat quality traits in pigs.

/pdf/genome-wide-association-analysis-of-meat-quality-traits-in-a-12g9cfg88y.pdf

Genome-wide association analysis of meat quality traits in a porcine Large White × Minzhu intercross population

TMT-based quantitative proteomic analysis of porcine muscle associated with postmortem meat quality

Runs of homozygosity (ROH) are contiguous homozygous genotype segments in the genome that are present in an individual since the identical haplotypes are inherited from each parent. The aim of this study was to investigate the frequency and distribution of ROH in the genomes of Landrace, Songliao black and Yorkshire pigs. We calculated two types of genome inbreeding coefficients and their correlation, including the inbreeding coefficient based on ROH (FROH) and the inbreeding coefficient based on the difference between the observed and expected number of homozygous genotypes (FHOM). Furthermore, we identified candidate genes in the genomic region most associated with ROH. We identified 21,312 ROH in total. The average number of ROH per individual was 32.99 ± 0.38 and the average length of ROH was 6.40 ± 0.070 Mb in the three breeds. The FROH results showed that Yorkshire pigs exhibited the highest level of inbreeding (0.092 ± 0.0015) and that Landrace pigs exhibited the lowest level of inbreeding (0.073 ± 0.0047). The average correlation between FROH and FHOM was high (0.94) within three breeds. The length of ROH provides insight into the inbreeding history of these three pig breeds. In this study, Songliao black pigs presented a higher frequency and average length of long ROH (>40 Mb) compared with those of Landrace and Yorkshire pigs, which indicated greater inbreeding in recent times. Genes related to reproductive traits (GATM, SPATA46, HSD17B7, VANGL2, DAXX, CPEB1), meat quality traits (NR1I3, APOA2, USF1) and energy conversion (NDUFS2) were identified within genomic regions with a high frequency of ROH. These genes could be used as target genes for further marker-assisted selection and genome selection.

https://www.mdpi.com/2076-2615/9/8/518/pdf

Genome-Wide Scan for Runs of Homozygosity Identifies Candidate Genes in Three Pig Breeds.

Fat-tailed sheep have a unique characteristic of depositing fat in their tails. In the present study, we conducted genome-wide association studies (GWAS) on traits related to tail fat deposition and body size in the Hulun Buir sheep. A total number of 300 individuals belonging to two fat-tailed lines of the Hulun Buir sheep breed genotyped with the Ovine Infinium HD SNP BeadChip were included in the current study. Two mixed models, one for continuous and one for binary phenotypic traits, were employed to analyse ten traits, that is, body length (BL), body height (BH), chest girth (CG), tail length (TL), tail width (TW), tail circumference (TC), carcass weight (CW), tail fat weight (TF), ratio of CW to TF (RCT) and tail type (TT). We identified 7, 6, 7, 2, 10 and 1 SNPs significantly associated with traits TF, CW, RCT, TW, TT and CG, respectively. Their associated genomic regions harboured 42 positional candidate genes. Out of them, 13 candidate genes including SMURF2, FBF1, DTNBP1, SETD7 and RBM11 have been associated with fat metabolism in sheep. The RBM11 gene has already been identified in a previous study on signatures of selection in this specific sheep population. Two more genes, that is, SMARCA5 and GAB1 were associated with body size in sheep. The present study has identified candidate genes that might be implicated in tail fat deposition and body size in sheep.

Genome-wide association studies revealed candidate genes for tail fat deposition and body size in the Hulun Buir sheep

As one of the main breeding selection criteria, external appearance has special economic importance in the hog industry. In this study, an Illumina Porcine SNP60 BeadChip was used to conduct a genome-wide association study (GWAS) in 605 pigs of the F2 generation derived from a Large White × Minzhu intercross. Traits under study were abdominal circumference (AC), body height (BH), body length (BL), cannon bone circumference (CBC), chest depth (CD), chest width (CW), rump circumference (RC), rump width (RW), scapula width (SW), and waist width (WW). A total of 138 SNPs (the most significant being MARC0033464) on chromosome 7 were found to be associated with BH, BL, CBC, and RC (P-value  = 4.15E-6). One SNP on chromosome 1 was found to be associated with CD at genome-wide significance levels. The percentage phenotypic variance of these significant SNPs ranged from 0.1–25.48%. Moreover, a conditional analysis revealed that the significant SNPs were derived from a single quantitative trait locus (QTL) and indicated additional chromosome-wide significant association for 25 SNPs on SSC4 (BL, CBC) and 9 SNPs on SSC7 (RC). Linkage analysis revealed two complete linkage disequilibrium haplotype blocks that contained seven and four SNPs, respectively. In block 1, the most significant SNP, MARC0033464, was present. Annotations from pig reference genome suggested six genes (GRM4, HMGA1, NUDT3, RPS10, SPDEF and PACSIN1) in block 1 (495 kb), and one gene (SCUBE3) in block 3 (124 kb). Functional analysis indicated that HMGA1 and SCUBE3 genes are the potential genes controlling BH, BL, and RC in pigs, with an application in breeding programs. We screened several candidate intervals and genes based on SNP location and gene function, and predicted their function using bioinformatics analyses.

/pdf/genome-wide-association-studies-identify-the-loci-for-5-1f17ptem82.pdf

Lixian Wang

Papers

Genome-wide association analysis of meat quality traits in a porcine Large White × Minzhu intercross population

TMT-based quantitative proteomic analysis of porcine muscle associated with postmortem meat quality

Genome-Wide Scan for Runs of Homozygosity Identifies Candidate Genes in Three Pig Breeds.

Genome-wide association studies revealed candidate genes for tail fat deposition and body size in the Hulun Buir sheep

Genome-wide association studies identify the loci for 5 exterior traits in a Large White × Minzhu pig population.