Abstract
The Y chromosome is the most gene-deficient chromosome in the human genome (though not the smallest chromosome) and has largely been sequestered away from large-scale studies of the effects ...of genetics on human health. Here I review the literature, focusing on the last 2 years, for recent evidence of the role of the Y chromosome in protecting from or contributing to disease. Although many studies have focused on Y chromosome gene copy number and variants in fertility, the role of the Y chromosome in human health is now known to extend too many other conditions including the development of multiple cancers and Alzheimer’s disease. I further include the discussion of current technology and methods for analyzing Y chromosome variation. The true role of the Y chromosome and associated genetic variants in human disease will only become clear when the Y chromosome is integrated into larger studies of human genetic variation, rather than being analyzed in isolation.
Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) ...have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called 'stem' cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks.
Dollars and sense There is an ongoing debate, and data investigation, into the uneven distribution of grant dollars and the impact it has. A study of the scientific impact of research funded by the ...Natural Sciences and Engineering Research Council of Canada (NSERC), focusing on individual researchers from three fields, concluded that impact per dollar generally decreased with increasing grant size 2. Similarly, a study of funding allocated by the National Institute of General Medical Sciences (NIGMS) from the National Institutes of Health reported that past $700,000 in annual direct cost to the investigator per year, productivity plateaus 3. Productivity was measured using a combination of publications and citations in both articles. Funding rates across agencies are historically low, and these studies show that exceedingly large grants are inefficient. Large grants, though perhaps not exceedingly large grants, will continue to be needed to fund many areas of research, especially including support for personnel. In contrast, crowdfunding has the potential to support small projects effectively. Crowdfunding is not a replacement or even a competition to typical funding mechanisms, but a complement. Most crowdfunding is quite small, with a median of $3500 funded per project on one platform, Experiment.com 4. The scale and scope of research questions that can be asked with crowdfunding are different from larger funded projects, but then, I would argue the audience is also different. When I decided to run a crowdfunding campaign to fund our work, I was an early career researcher, I had not been awarded funding from any major funding body, and we had been denied multiple times. For our project, I also had funding for personnel, and had collected samples, but needed funding for particular components of the research. The project was primed for crowdfunding. However, in the same way as there is a lot to learn that can help in crafting better grant proposals, there are many things to learn and prepare for when embarking on crowdfunding, and a lot of advice out there 5.
Searching for sex differences Wilson, Melissa A.
Science (American Association for the Advancement of Science),
09/2020, Volume:
369, Issue:
6509
Journal Article
Peer reviewed
Open access
Evolved sex differences in gene expression are pervasive, but so too is sampling bias
The behemoth effort, started a decade ago, known as the Genotype-Tissue Expression (GTEx) Consortium aims to ...discover how DNA variation affects gene expression across human tissues (
1
,
2
). As part of this consortium, on page 1331 of this issue, Oliva
et al.
(
3
) find that more than one-third of genes show sex-biased expression in at least one tissue. Four other GTEx studies, on pages 1318, 1334, 1333, and 1332 of this issue, respectively, discuss the effects of gene regulation in human tissues (
4
), identify functional rare genetic variation (
5
), study predictors of telomere length (
6
), and report cell type–specific gene regulation (
7
). What is especially notable about Oliva
et al.
is the careful analysis, which revealed that in addition to reported genetic and hormonal effects (
8
), there are cell type–specific sex differences in tissue composition. Furthermore, their work highlights that rather than being strictly dimorphic, interindividual variation results in overlapping distributions of gene expression between the sexes.
We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including ...single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.
The presence of fetal cells has been associated with both positive and negative effects on maternal health. These paradoxical effects may be due to the fact that maternal and offspring fitness ...interests are aligned in certain domains and conflicting in others, which may have led to the evolution of fetal microchimeric phenotypes that can manipulate maternal tissues. We use cooperation and conflict theory to generate testable predictions about domains in which fetal microchimerism may enhance maternal health and those in which it may be detrimental. This framework suggests that fetal cells may function both to contribute to maternal somatic maintenance (e.g. wound healing) and to manipulate maternal physiology to enhance resource transmission to offspring (e.g. enhancing milk production). In this review, we use an evolutionary framework to make testable predictions about the role of fetal microchimerism in lactation, thyroid function, autoimmune disease, cancer and maternal emotional, and psychological health. Also watch the Video Abstract.
The human Y chromosome exhibits surprisingly low levels of genetic diversity. This could result from neutral processes if the effective population size of males is reduced relative to females due to ...a higher variance in the number of offspring from males than from females. Alternatively, selection acting on new mutations, and affecting linked neutral sites, could reduce variability on the Y chromosome. Here, using genome-wide analyses of X, Y, autosomal and mitochondrial DNA, in combination with extensive population genetic simulations, we show that low observed Y chromosome variability is not consistent with a purely neutral model. Instead, we show that models of purifying selection are consistent with observed Y diversity. Further, the number of sites estimated to be under purifying selection greatly exceeds the number of Y-linked coding sites, suggesting the importance of the highly repetitive ampliconic regions. While we show that purifying selection removing deleterious mutations can explain the low diversity on the Y chromosome, we cannot exclude the possibility that positive selection acting on beneficial mutations could have also reduced diversity in linked neutral regions, and may have contributed to lowering human Y chromosome diversity. Because the functional significance of the ampliconic regions is poorly understood, our findings should motivate future research in this area.
Abstract
Levels and patterns of genetic diversity can provide insights into a population’s history. In species with sex chromosomes, differences between genomic regions with unique inheritance ...patterns can be used to distinguish between different sets of possible demographic and selective events. This review introduces the differences in population history for sex chromosomes and autosomes, provides the expectations for genetic diversity across the genome under different evolutionary scenarios, and gives an introductory description for how deviations in these expectations are calculated and can be interpreted. Predominantly, diversity on the sex chromosomes has been used to explore and address three research areas: 1) Mating patterns and sex-biased variance in reproductive success, 2) signatures of selection, and 3) evidence for modes of speciation and introgression. After introducing the theory, this review catalogs recent studies of genetic diversity on the sex chromosomes across species within the major research areas that sex chromosomes are typically applied to, arguing that there are broad similarities not only between male-heterogametic (XX/XY) and female-heterogametic (ZZ/ZW) sex determination systems but also any mating system with reduced recombination in a sex-determining region. Further, general patterns of reduced diversity in nonrecombining regions are shared across plants and animals. There are unique patterns across populations with vastly different patterns of mating and speciation, but these do not tend to cluster by taxa or sex determination system.
Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment ...of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC.
Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses.
By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression.
Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.
Cancer immunotherapy with immune checkpoint blockade (CKB) is now standard of care for multiple cancers. The clinical response to CKB is associated with T cell immunity targeting cancer-induced ...mutations that generate novel HLA-binding epitopes (neoepitopes).
Here, we developed a rapid bioinformatics pipeline and filtering strategy, EpitopeHunter, to identify and prioritize clinically relevant neoepitopes from the landscape of somatic mutations. We used the pipeline to determine the frequency of neoepitopes from the TCGA dataset of invasive breast cancers. We predicted HLA class I-binding neoepitopes for 870 breast cancer samples and filtered the neoepitopes based on tumor transcript abundance.
We found that the total mutational burden (TMB) was highest for triple-negative breast cancer, TNBC, (median = 63 mutations, range: 2-765); followed by HER-2(+) (median = 39 mutations, range: 1-1206); and lowest for ER/PR(+)HER-2(-) (median = 32 mutations, range: 1-2860). 40% of the nonsynonymous mutations led to the generation of predicted neoepitopes. The neoepitope load (NEL) is highly correlated with the mutational burden (R
= 0.86).
Only half (51%) of the predicted neoepitopes are expressed at the RNA level (FPKM≥2), indicating the importance of assessing whether neoepitopes are transcribed. However, of all patients, 93% have at least one expressed predicted neoepitope, indicating that most breast cancer patients have the potential for neo-epitope targeted immunotherapy.
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