14 research outputs found
GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.
Funder: Department of HealthMosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10-10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10-12), 4 kg higher fat mass (p = 1.3 × 10-4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10-4) and 4.5 kg lower handgrip strength (p = 4.7 × 10-7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health
Mps1 Phosphorylates Its N-Terminal Extension to Relieve Autoinhibition and Activate the Spindle Assembly Checkpoint
Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC. Whether the NTE regulates other mitotic functions of Mps1 remains unknown. Here, we report that phosphorylation within the NTE contributes to Mps1 activation through relief of catalytic autoinhibition that is mediated by the NTE itself. Moreover, we find that this regulatory NTE function is independent of its role in Mps1 kinetochore recruitment. We demonstrate that the NTE autoinhibitory mechanism impinges most strongly on Mps1-dependent SAC functions and propose that Mps1 activation likely occurs sequentially through dimerization of a “prone-to-autophosphorylate” Mps1 conformer followed by autophosphorylation of the NTE prior to maximal kinase activation segment trans-autophosphorylation. Our observations underline the importance of autoregulated Mps1 activity in generation and maintenance of a robust SAC in human cells
Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus
: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success
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Using human genomics to decipher biological mechanisms underlying reproductive ageing and fertility in women
Women are born with a non-renewable ovarian reserve, which is depleted throughout
reproductive life. When this reserve is exhausted, they experience menopause and cease ovulating.
Importantly, menopause timing is highly variable and can impact health outcomes in later life. One in 100
women experience menopause before the age of 40. As natural fertility begins to decline 10 years prior to
menopause, the age of menopause impacts reproductive options for many women, leading to increased
demand for fertility treatments, which have low success rate. This is especially important as more women
delay childbearing. Endocrine and imaging tests used in the clinical setting only record changes in ovarian
function that have already taken place, thus disabling early prediction and timely identification of women
with reduced reproductive lifespan. Human genetic studies have attempted to overcome this problem by
identifying genetic markers associated with menopause timing and thus providing substantial insight into
the biological mechanisms governing ovarian ageing. However, previous approaches have been largely
restricted to assessing common genetic variation, leaving many aspects of the trait biology unexplored.
This dissertation describes five distinct projects that advance our understanding of the genetic
determinants of female reproductive ageing by employing state-of-art genomic and proteomic
technologies with robust functional models.
Chapter 3 uses whole exome sequence data to identify rare protein-coding variants associated with
menopause timing in ~120K women in the UK Biobank (UKBB), and implicates five novel ANM genes
with effect sizes up to ~5 times larger than previously discovered for common variants. Notably,
heterozygous loss of ZNF518A shortens reproductive lifespan by delaying puberty timing in girls and
reducing ANM by nearly 6 years in carriers, an effect larger than any variation currently tested in clinical
genetics for premature ovarian ageing. Furthermore, I provide evidence that ZNF518A is a master
transcriptional regulator of ovarian development and establishment of the ovarian reserve in foetal life,
thus highlighting novel mechanisms involved in ANM aetiology. I also identify a new cancer
predisposition gene, SAMHD1, which has a comparable effect size in women and men to well-established
genes such as CHEK2, further reinforcing the link between cancer and reproductive ageing. Finally, I
show that mothers with genetic susceptibility to earlier ovarian ageing have a higher rate of de novo
mutations in their offspring. This provides direct evidence that female germline mutation rate is heritable
and highlights a mechanism for maternal effects on offspring health. Chapter 4 extends the exome
sequence analysis to an extreme form of early menopause, i.e. POI, which is often considered a
monogenic disorder, with pathogenic mutations reported in ~100 genes. However, such reports are based
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on small numbers of individuals without independent replication, or/and no functional validation. I
systematically evaluate the penetrance of these reported genes in ~120K UKBB women, 2,231 of whom
reported ANM before age 40. In this largest study of POI to date, I find limited evidence to support any
previously reported autosomal dominant gene. For nearly all these genes I could rule out even modest
penetrance, with 97.8% of all identified protein truncating variants found in reproductively healthy
women with ANM over 40. In addition, I demonstrate novel haploinsufficiency effects in studied POI
genes, including TWNK and SOHLH2. Collectively my results suggest that most POI cases are likely
oligogenic or polygenic in nature, which has major implications for future clinical genetic testing and
counselling. Chapter 5 presents the first proteogenomic study for the ANM targeting 4,775 distinct
proteins measured from plasma samples of 10,713 European ancestry individuals in the Fenland study.
Although this analysis did not identify robust protein candidates associated with ANM, it demonstrates
the potential of such approaches to discover new biomarkers. Chapter 6 presents the largest genomic
meta-analysis for age at menarche on ~566,000 women of European ancestry and 696 genomic loci that
contribute to regulation of menarche timing. I use this data to explore biological mechanisms and overlap
between genetic architectures of reproductive health outcomes. I provide the first evidence on the
enrichment of DDR mechanisms for menarche timing, indicating the involvement of DDR in regulation
of both extremes of reproductive lifespan, i.e. menarche and menopause. In addition, I report first gene
candidates that I speculate may act via oocyte-specific mechanisms to modify reproductive longevity. I
also highlight DDR and other novel mechanisms, including ribosome biogenesis, which impact multiple
reproductive health outcomes, such as polycystic ovarian syndrome (PCOS), twinning and number of
children (NEB). Finally, I demonstrate the first population genomic evidence on the role of DDR related
mechanisms in various anthropometric, metabolic and reproductive health outcomes, indicating that DDR
could act as a marker of health outcomes beyond cancer. Combining human genomic evidence with
cutting edge CRISPR technology and the In vitro gametogenesis system, in Chapter 7 I investigate the
role of PARP-1 in proliferation of primordial germ cells during the establishment of the ovarian reserve. I
demonstrate suggestive evidence on the role of PARP-1 in decreasing ANM in women and, paradoxically,
that deletion of PARP-1 increases the efficiency of primordial germ cell production in vitro. I speculate
that, despite the initial increase in primordial germ cells in the PARP-1 knockout, the quality of these cells
could be compromised, thus ultimately limiting the functional ovarian pool. Collectively, these findings
provide significant insights into the biological processes of reproductive ageing in women and have the
potential to guide future experimental work aimed towards identification of new therapies for enhancing
reproductive function and preserving fertility in women, as well as designing intervention strategies to
prevent or diminish menopause-related health outcomes
Influence of Three Different Surgical Techniques on Microscopic Damage of Saphenous Vein Grafts—A Randomized Study
Background and Objectives: The saphenous vein is one of the most common used grafts (SVG) for surgical revascularization. The mechanism of the SVGs occlusion is still unknown. Surgical preparation techniques have an important role in the early and late graft occlusion. Our study analyzed the influence of the three different surgical techniques on the histological and immunohistochemical characteristics of the vein grafts. Methods: Between June 2019 and December 2020, 83 patients who underwent surgical revascularization were prospectively randomly assigned to one of the three groups, according to saphenous vein graft harvesting (conventional (CVH), no-touch (NT) and endoscopic (EVH)) technique. The vein graft samples were sent on the histological (hematoxylin-eosin staining) and immunohistochemical (CD31, Factor VIII, Caveolin and eNOS) examinations. Results: The CVH, NT, and EVH groups included 27 patients (mean age 67.66 ± 5.6), 31 patients (mean age 66.5 ± 7.4) and 25 patients (mean age 66 ± 5.5), respectively. Hematoxylin-eosin staining revealed a lower grade of microstructural vein damage in the NT group (2, IQR 1-2) in comparison with CVH and EVH (3, IQR 2-4), (4, IQR 2-4) respectively (p p = 0.02, FVIII, p p = 0.001, and eNOS, p = 0.003). Conclusion: The best preservation of the structural vein integrity was in the NT group, while the lowest rate of leg wound complication was in the EVH group. These facts increase the interest in developing and implementing the endoscopic no-touch technique
Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes.
Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency < 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (GCK, GIGYF1, HNF1A) in addition to missense variants in ZEB2 (n = 31 carriers; odds ratio [OR] = 5.5 [95% confidence interval = 2.5-12.0]; p = 6.4 × 10-7), MLXIPL (n = 245; OR = 2.3 [1.6-3.2]; p = 3.2 × 10-7), and IGF1R (n = 394; OR = 2.4 [1.8-3.2]; p = 1.3 × 10-10). Carriers of damaging missense variants within IGF1R were also shorter (-2.2 cm [-1.8 to -2.7]; p = 1.2 × 10-19) and had higher circulating insulin-like growth factor-1 (IGF-1) protein levels (2.3 nmol/L [1.7-2.9]; p = 2.8 × 10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance was supported by Mendelian randomization analyses using common variants. These results increase understanding of the genetic architecture of T2D and highlight the growth hormone/IGF-1 axis as a potential therapeutic target.This work was funded by the Medical Research Council (Unit programs: MC_UU_12015/2, MC_UU_00006/2, MC_UU_12015/1, and MC_UU_00006/1). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). S.L. is supported by a Wellcome Trust Clinical PhD Fellowship (225479/Z/22/Z). S.O. is supported by a Wellcome Investigator Award (214274/Z/19/Z)
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Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.
Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10-6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10-4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI
Genetic insights into biological mechanisms governing human ovarian ageing
Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease
Understanding the genetic complexity of puberty timing across the allele frequency spectrum
Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ∼800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ∼11 and ∼14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ∼220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83 , which we demonstrate amplifies signaling of MC3R , a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease. </p