Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Karyotype evolution in vivo and in vitro

The present thesis is divided into two parts; the first part, comprising chapters 1 to 4, called "Theoretical considerations on karyotype evolution in mammals", and the second part, chapters 5 and 6, called "Karyotype evolution in cell lines". All the chapters are selfcontained and have their own lists of references. The first three chapters deal with different population genetical aspects arising from the reduced fertility of chromosomal heterozygotes relative to chromosomal homozygotes. In chapter 1, after an introduction about karyotypes and chromosome mutations, various factors which can influence the behaviour of a chromosome mutation in a population are considered. The probabilities are given for a chromosome mutation to become fixed in a small population due to random genetic drift, and the conditions are specified under which segregation distortion, viability advantage and recombination modification can help a chromosome mutation to increase in frequency in a large, random mating population. Chapter 2 brings up to discussion the factors which determine the fertility disadvantage of chromosomal heterozygotes. The role of the reproductive system in influencing the effective fertility of individuals which produce lethal but functional gametes is stressed. In the last part of chapter 2 we describe how the fitness disadvantage associated with human chromosome mutations can be estimated. The importance of chromosome mutations in the speciation process is debated in chapter 3. According to a common idea, chromosome mutations are important for speciation because they can help to decrease the effective gene-flow between two partially separated populations. However, there are a number of problems associated with this view. The main obstacle is the rather small effect of karyotype differences on gene-flow between two populations; this is shown in chapter 3 with a simple mathematical model. The chapter ends with us turning the question around through arguing that a chromosome mutation may have a much better chance to spread in a speciation situation, which implies that speciation is important for chromosome mutations rather than the reverse. Chapter 4 is a short chapter introducing the use of nonparametric statistics to karyotype research. We here show that there exists a significantly high proportion of mammalian karyotypes containing acrocentric and bi-armed chromosomes in a non-random mixture. The result is perhaps not very surprising, but the chapter should indicate that this approach to karyotype research can be fruitfully continued, given more data and the help of a computer. The results obtained from an investigation of a series of human intraspecific hybrids made between lymphocytes and D98/AH-2 cells are described in chapter 5. The author of this thesis did most of the tissue culture work involved and the karyotype analysis. Special effort was put into determining and describing karyotypic and genetic – enzyme and immunological – markers of the hybrid cells. All the hybrid lines were karyotypically very stable, and the karyotype evolution of one line, DM, was closely followed during more than 500 days of growth in culture. A number of 6-thioguanine resistent lines were isolated, and examples are given which show how such segregant lines can be used for genetic analysis of the human genome. Established cell lines grown under constant conditions normally reach a kind of equilibrium in respect to the karyotypes of the cells in the cell line. The equilibrium is characterized by almost all cells having different but, at the same time, similar karyotypes. In chapter 6 is proposed a model which we hope can be used to describe such situations of variability and stability. Based on the idea that there is one type of cells in the cell line which is ideal and that there are many ways by which cells can differ from the ideal type of cells, this model is in certain aspects very crude. It is, however, the first model of its kind, as far as we know, and other models which try to be interpretable must probably be based on premises very similar to the ones used in chapter 6.</p

Mellan natur och kultur

Abstract is not available

Asex and Evolution: A Very Large-Scale Overview

Asexuals come in all sorts. In this personal overview, I identify asexual organisms with eukaryotes that do not regularly go through the meiotic cycle. Such organisms may be asexual in many different ways and of many different reasons. The spread of asexuality is therefore always a unique process, and any notion of a general evolutionary advantage for asexuality is at best misleading. In discussions on the evolution of asexuality, ideas about genetic conflicts are often more helpful than notions about “costs”. Many asexuals are associated with different fitness problems, and most of them are not particularly good at being asexual either. Their absence of long-term evolutionary success follows from their lack of recombination, leading to complex effects involving drift and selection that we are just beginning to understand. The interest in asexual organisms comes not from what they say about sex, but from what they say about living as a eukaryote