Selection and Metabolic Disease in the Pacific

An example of a "signature of selection" in a population is a region of the genome that exhibits a reduction in genetic variability with a particular linkage disequilibrium pattern. This reduction in variation can arise when the phenotype of a neutral beneficial allele experiences a favourable change in environmental conditions. This results in an increased frequency of both the allele, and linked sites, within a population. Polynesian populations share a common genetic ancestry with East Asia, but little characterisation of genetic selection has been undertaken in Polynesian populations. Serum urate has been associated with metabolic disorders such as obesity, type 2 diabetes, renal disease and metabolic syndrome. It is hypothesised that serum urate may have undergone positive selection in Polynesians due to some of the beneficial properties, such as its role as an anti-oxidant, or as an adjuvant for the innate immune system. New Zealand Polynesians have inherently elevated serum urate levels and increased rates of gout. This thesis presents the results of a genome-wide study of selection in Polynesian (and other) populations, focusing on testing the hypothesis that genomic loci containing genes involved in urate processing have undergone selection. There was no evidence of wide-spread selection at genes associated with urate and gout, or related metabolic disorders, but there was evidence at some individual loci. Pathway analysis showed that of the significant pathways, there was a dominance of metabolic pathways that were enriched for genes with signatures of selection. Calcium related transport and signalling was a theme amongst loci that displayed signs of possible selection. Regions of the genome that were possibly selected in modern-day Polynesian populations also had similarities to those of modern-day East Asian populations. This thesis has provided identification and characterisation of regions in the genome with possible evidence of genetic selection in Polynesian populations, that previously was not available. It has also provided insight into the role of genetic selection with respect to urate and metabolic disease

A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions

PurposeCorneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.DesignCase series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.ParticipantsFour ERED families, including 28 affected and 17 unaffected individuals.MethodsHumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle–niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.Main Outcome MeasuresLinkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.ResultsLinkage microarray analysis identified a candidate region on chromosome chr10:12,576,562–112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ–TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.ConclusionsThe COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium

Identification of Cis-Regulatory Modules that Function in the Male Germline of Flowering Plants.

The male germline of flowering plants develops within the vegetative cell of the male gametophyte and displays a distinct transcriptional profile. Key to understanding the development of this unique cell lineage is determining how gene expression is regulated within germline cells. This knowledge impacts upon our understanding of cell specification, differentiation, and plant fertility. Here, we describe methods to identify cis-regulatory modules (CRMs) that act as key regulatory regions in the promoters of germline-expressed genes. We detail the complimentary techniques of phylogenetic footprinting and the use of fluorescent reporters in pollen for the identification and verification of CRMs

Interactions between serum urate-associated genetic variants and sex on gout risk: analysis of the UK Biobank

Abstract Background Sex-specific differences in the effect of genetic variants on serum urate levels have been described. The aim of this study was to systematically examine whether serum urate-associated genetic variants differ in their influence on gout risk in men and women. Methods This research was conducted using the UK Biobank Resource. Thirty single nucleotide polymorphisms (SNPs) associated with serum urate were tested for their association with gout in men and women of European ancestry, aged 40–69 years. Gene-sex interactions for gout risk were analysed using an interaction analysis in logistic regression models. Results Gout was present in 6768 (4.1%) men and 574 (0.3%) women, with an odds ratio (95% confidence interval) for men 13.42 (12.32–14.62) compared with women. In men, experiment-wide association with gout was observed for 21 of the 30 serum urate-associated SNPs tested, and in women for three of the 30 SNPs. Evidence for gene-sex interaction was observed for ABCG2 (rs2231142) and PDZK1 (rs1471633), with the interaction in ABCG2 driven by an amplified effect in men and in PDZK1 by an absence of effect in women. Similar findings were observed in a sensitivity analysis which excluded pre-menopausal women. For the other SNPs tested, no significant gene-sex interactions were observed. Conclusions In a large population of European ancestry, ABCG2 and PDZK1 gene-sex interactions exist for gout risk, with the serum urate-raising alleles exerting a greater influence on gout risk in men than in women. In contrast, other serum urate-associated genetic variants do not demonstrate significant gene-sex interactions for gout risk

Lack of direct evidence for natural selection at the candidate thrifty gene locus, PPARGC1A

Background: The gene PPARGC1A, in particular the Gly482Ser variant (rs8192678), had been proposed to be subject to natural selection, particularly in recent progenitors of extant Polynesian populations. Reasons include high levels of population differentiation and increased frequencies of the derived type 2 diabetes (T2D) risk 482Ser allele, and association with body mass index (BMI) in a small Tongan population. However, no direct statistical tests for selection have been applied

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

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