A Method to Find Longevity-Selected Positions in the Mammalian Proteome

Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conserved in long-lived but not short-lived mammal species. We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-Müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and a homology model of the kinase domain shows that its longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein’s activity in a lifespan-specific manner

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetics of ovarian ageing : genetic association studies on natural menopause and primary ovarian insufficiency

Menopause is the endpoint of a process referred to as ovarian ageing. The mean age at menopause is approximately 51 years, but varies widely between 40 to 60 years of age. Approximately 1% of all women experience menopause before the age of 40, which is a condition known as primary ovarian insufficiency (POI). Timing of menopause has great implications for female fertility and general health (e.g. osteoporosis and cardiovascular disease). Although the exact physiological processes underlying the timing of menopause are far from elucidated at present, genetic factors have proven to play a major role in determining this variation in menopausal age. The identification of genetic variants associated with (early) ovarian ageing and thereby infertility and consequences for health later in life, constitutes the core of this thesis. To identify genetic variants in timing of (early) menopause, four candidate gene association studies on single nucleotide polymorphisms (SNPs) and structural variants, a genome-wide association study (GWAS) and a gene-gene interaction analysis were conducted and are described in this thesis. In a candidate gene association study in five genes involved in primordial follicle recruitment conducted in 3616 postmenopausal women, the AMHR2 (in interaction with parity) and BMP15 gene were associated with timing of menopause. A subsequent gene-gene interaction analysis in these five genes identified an interaction between SNPs in the AMH and AMHR2 gene, suggesting a role of the AMH signaling pathway in the onset of natural menopause. The number of CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have been repeatedly associated with POI and account for approximately 1-8% of all cases of POI. It has been suggested that the number of FMR1 CGG repeats in the normal and intermediate range (up to 55 repeats) are also associated with (early) ovarian ageing. However, in a large population-based sample of 3611 postmenopausal women we found no association between the number of FMR1 CGG repeats and age at menopause. Also, in a case-control study of 375 women with idiopathic POI and 3368 controls with natural menopause above 40 years of age, no association was found between normal and intermediate ranged CGG repeats in the FMR1 gene and the risk of POI. Together, these results question the role of FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process. In a GWAS conducted in a cohort of 901 European idiopathic POI and early menopause (EM) cases compared to 2209 controls with an age at natural menopause over 45 years, the strongest association was seen in a locus near the BRSK1 gene on chromosome 19. Interestingly, this locus was previously identified in GWAS in natural menopause above 40 years. This finding supports the evidence that POI, EM and normal menopause share at least a proportion of their genetic aetiology. Additionally, a number of potentially interesting specific loci for POI and EM were identified, including NELL1, PGCF5, MTM1 and MTMR

Glucocorticoids modulate the response of ornithine decarboxylase to unilateral removal of the dorsal hippocampus

The effect of unilateral removal of the dorsal hippocampus and of glucocorticoid administration was measured on the activity of ornithine decarboxylase (ODC) in the remaining contralateral hippocampus lobe. Unilateral hippocampectomy (Hx) resulted in a rapid rise of ODC activity in the contralateral lobe. The effect on ODC was maximal at 6 h after surgery and lasted two days. In the absence of the adrenals the effect of Hx on the enzyme was more potent and more prolonged. Elevated ODC activity was still detectable at 5 days after surgery, but not at 10 days. Chronic replacement with dexamethasone (DEX) offered in drinking water decreased the Hx-induced ODC response of ADX rats at 3 days after surgery to the level of enzyme activity observed in the S-ADX Hx subject. The effect of the steroid seemed related to the extent of occupation of the pool of glucocorticoid receptor sites in cytosol of rat hippocampus. In contrast, a single injection of a high dose of DEX to Hx-ADX animals at 3 days after surgery increased ODC activity in addition to the lesion-induced ODC in the contralateral lobe. It is concluded that after unilateral removal of the dorsal hippocampus ODC is a biochemical marker for cellular responses taking place in the contralateral lobe. Glucocorticoids modulate the lesion-induced ODC response

Glucocorticoids modulate the response of ornithine decarboxylase to unilateral removal of the dorsal hippocampus

The effect of unilateral removal of the dorsal hippocampus and of glucocorticoid administration was measured on the activity of ornithine decarboxylase (ODC) in the remaining contralateral hippocampus lobe. Unilateral hippocampectomy (Hx) resulted in a rapid rise of ODC activity in the contralateral lobe. The effect on ODC was maximal at 6 h after surgery and lasted two days. In the absence of the adrenals the effect of Hx on the enzyme was more potent and more prolonged. Elevated ODC activity was still detectable at 5 days after surgery, but not at 10 days. Chronic replacement with dexamethasone (DEX) offered in drinking water decreased the Hx-induced ODC response of ADX rats at 3 days after surgery to the level of enzyme activity observed in the S-ADX Hx subject. The effect of the steroid seemed related to the extent of occupation of the pool of glucocorticoid receptor sites in cytosol of rat hippocampus. In contrast, a single injection of a high dose of DEX to Hx-ADX animals at 3 days after surgery increased ODC activity in addition to the lesion-induced ODC in the contralateral lobe. It is concluded that after unilateral removal of the dorsal hippocampus ODC is a biochemical marker for cellular responses taking place in the contralateral lobe. Glucocorticoids modulate the lesion-induced ODC response.</p