On the power to detect rare recombination events Wright, Alison E.; Darolti, Iulia; Bloch, Natasha I. ...
Proceedings of the National Academy of Sciences,
06/2019, Letnik:
116, Številka:
26
Journal Article
High-throughput sequencing (HTS) of immunoglobulin (B-cell receptor, antibody) and T-cell receptor repertoires has increased dramatically since the technique was introduced in 2009 (1-3). This ...experimental approach explores the maturation of the adaptive immune system and its response to antigens, pathogens, and disease conditions in exquisite detail. It holds significant promise for diagnostic and therapy-guiding applications. New technology often spreads rapidly, sometimes more rapidly than the understanding of how to make the products of that technology reliable, reproducible, or usable by others. As complex technologies have developed, scientific communities have come together to adopt common standards, protocols, and policies for generating and sharing data sets, such as the MIAME protocols developed for microarray experiments. The Adaptive Immune Receptor Repertoire (AIRR) Community formed in 2015 to address similar issues for HTS data of immune repertoires. The purpose of this perspective is to provide an overview of the AIRR Community's founding principles and present the progress that the AIRR Community has made in developing standards of practice and data sharing protocols. Finally, and most important, we invite all interested parties to join this effort to facilitate sharing and use of these powerful data sets (join@airr-community.org).
Abstract
Many models of evolution by sexual selection predict a coevolution of sensory systems and mate preferences, but the genomic architecture (number and arrangement of contributing loci) ...underlying these characters could constrain this coevolution. Here, we examine how the genomic organization and evolution of the opsin genes (responsible for tuning color vision) can influence the evolutionary trajectory of sexually selected traits across 15 species in the family Poeciliidae, which includes classic systems for studies of color-mediated sexual selection such as guppies, swordtails, and mollies. Although male coloration patterns and the importance of this coloration in female mate choice vary widely within and among genera, sequencing revealed low variability at amino acid sites that tune Long Wavelength-Sensitive (LWS) opsins in this speciose family. Although most opsin genes in these species appear to have evolved along traditional mutation-selection dynamics, we identified high rates of gene conversion between two of the LWS loci (LWS-1 and LWS-3), likely due to the inverted tandem repeat nature of these genes. Yet members of the subgenus Lebistes appear to resist LWS gene conversion. The LWS opsins are responsible for detecting and discriminating red and orange coloration—a key sexually selected trait in members of the subgenus Lebistes. Taken together these results suggest selection is acting against the homogenizing effects of gene conversion to maintain LWS-1/LWS-3 differences within this subgenus.
It is increasingly clear that an extraordinarily diverse range of clinically important conditions-including infections, vaccinations, autoimmune diseases, transplants, transfusion reactions, aging, ...and cancers-leave telltale signatures in the millions of V(D)J-rearranged antibody and T cell receptor TR per the Human Genome Organization (HUGO) nomenclature but more commonly known as TCR genes collectively expressed by a person's B cells (antibodies) and T cells. We refer to these as the
. Because of its diversity and complexity, the immunome provides singular opportunities for advancing personalized medicine by serving as the substrate for a highly multiplexed, near-universal blood test. Here we discuss some of these opportunities, the current state of immunome-based diagnostics, and highlight some of the challenges involved. We conclude with a call to clinicians, researchers, and others to join efforts with the Adaptive Immune Receptor Repertoire Community (AIRR-C) to realize the diagnostic potential of the immunome.
The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility ...may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Trade-offs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction.
Immunoglobulins or antibodies are the main effector molecules of the B-cell lineage and are encoded by hundreds of variable (V), diversity (D), and joining (J) germline genes, which recombine to ...generate enormous IG diversity. Recently, high-throughput adaptive immune receptor repertoire sequencing (AIRR-seq) of recombined V-(D)-J genes has offered unprecedented insights into the dynamics of IG repertoires in health and disease. Faithful biological interpretation of AIRR-seq studies depends upon the annotation of raw AIRR-seq data, using reference germline gene databases to identify the germline genes within each rearrangement. Existing reference databases are incomplete, as shown by recent AIRR-seq studies that have inferred the existence of many previously unreported polymorphisms. Completing the documentation of genetic variation in germline gene databases is therefore of crucial importance. Lymphocyte receptor genes and alleles are currently assigned by the Immunoglobulins, T cell Receptors and Major Histocompatibility Nomenclature Subcommittee of the International Union of Immunological Societies (IUIS) and managed in IMGT
, the international ImMunoGeneTics information system
(IMGT). In 2017, the IMGT Group reached agreement with a group of AIRR-seq researchers on the principles of a streamlined process for identifying and naming inferred allelic sequences, for their incorporation into IMGT
. These researchers represented the AIRR Community, a network of over 300 researchers whose objective is to promote all aspects of immunoglobulin and T-cell receptor repertoire studies, including the standardization of experimental and computational aspects of AIRR-seq data generation and analysis. The Inferred Allele Review Committee (IARC) was established by the AIRR Community to devise policies, criteria, and procedures to perform this function. Formalized evaluations of novel inferred sequences have now begun and submissions are invited via a new dedicated portal (https://ogrdb.airr-community.org). Here, we summarize recommendations developed by the IARC-focusing, to begin with, on human IGHV genes-with the goal of facilitating the acceptance of inferred allelic variants of germline IGHV genes. We believe that this initiative will improve the quality of AIRR-seq studies by facilitating the description of human IG germline gene variation, and that in time, it will expand to the documentation of TR and IG genes in many vertebrate species.
Germline variation at immunoglobulin (IG) loci is critical for pathogen-mediated immunity, but establishing complete haplotype sequences in these regions has been problematic because of complex ...sequence architecture and diploid source DNA. We sequenced BAC clones from the effectively haploid human hydatidiform mole cell line, CHM1htert, across the light chain IG loci, kappa (IGK) and lambda (IGL), creating single haplotype representations of these regions. The IGL haplotype generated here is 1.25 Mb of contiguous sequence, including four novel IGLV alleles, one novel IGLC allele, and an 11.9-kb insertion. The CH17 IGK haplotype consists of two 644 kb proximal and 466 kb distal contigs separated by a large gap of unknown size; these assemblies added 49 kb of unique sequence extending into this gap. Our analysis also resulted in the characterization of seven novel IGKV alleles and a 16.7-kb region exhibiting signatures of interlocus sequence exchange between distal and proximal IGKV gene clusters. Genetic diversity in IGK/IGL was compared with that of the IG heavy chain (IGH) locus within the same haploid genome, revealing threefold (IGK) and sixfold (IGL) higher diversity in the IGH locus, potentially associated with increased levels of segmental duplication and the telomeric location of IGH.
High genetic diversity is thought to characterize successful invasive species, as the potential to adapt to new environments is enhanced and inbreeding is reduced. In the last century, guppies, ...Poecilia reticulata, repeatedly invaded streams in Australia and elsewhere. Quantitative genetic studies of one Australian guppy population have demonstrated high additive genetic variation for autosomal and Y-linked morphological traits. The combination of colonization success, high heritability of morphological traits, and the possibility of multiple introductions to Australia raised the prediction that neutral genetic diversity is high in introduced populations of guppies. In this study we examine genetic diversity at nine microsatellite and one mitochondrial locus for seven Australian populations. We used mtDNA haplotypes from the natural range of guppies and from domesticated varieties to identify source populations. There were a minimum of two introductions, but there was no haplotype diversity within Australian populations, suggesting a founder effect. This was supported by microsatellite markers, as allelic diversity and heterozygosity were severely reduced compared to one wild source population, and evidence of recent bottlenecks was found. Between Australian populations little differentiation of microsatellite allele frequencies was detected, suggesting that population admixture has occurred historically, perhaps due to male-biased gene flow followed by bottlenecks. Thus success of invasion of Australia and high additive genetic variance in Australian guppies are not associated with high levels of diversity at molecular loci. This finding is consistent with the release of additive genetic variation by dominance and epistasis following inbreeding, and with disruptive and negative frequency-dependent selection on fitness traits.
Vertebral development is a dynamic and complicated process, and defects can be caused by a variety of influences. Spinal curvature with no known cause (idiopathic scoliosis) affects 2–3% of the human ...population. In order to understand the etiology and pathogenesis of complex human skeletal defects such as idiopathic scoliosis, multiple models must be used to study all of the factors affecting vertebral stability and deformity. Although fish and humans have many of the same types of offenses to vertebral integrity, they have been overlooked as a resource for study. The most common morphological deformity reported for fish are those that occur during the development of the spinal system, and as with humans, curvature is a common morphological consequence. Here we review spinal curvature in teleosts and suggest that they are an unexploited resource for understanding the basic elements of vertebral stability, deformity, development and genetics. Fish can be a value to vertebral research because they are tractable, have a diversity of non-induced vertebral deformities, and substantial genomic resources. Current animal models lack non-induced deformities and the experimental tractability necessary for genetic studies. The fact that fish are free of an appendicular skeleton should allow for analysis of basic spinal integrity without the biomechanical constraints observed in quadrupedal and bipedal models. To illustrate the point we review human idiopathic scoliosis and the potential contribution teleosts can make for the identification of causes, risk factors, and treatment options.
Summary Human familial/idiopathic-type scoliosis (IS) is a complex genetic disorder for which the cause is unknown. The curve phenotype characteristically demonstrates pronounced morphological and ...developmental variability that is likely a consequence of biomechanical, environmental, and genetic differences between individuals. In addition, risk factors that affect the propensity for curves to progress to severity are unknown. Progress in understanding the fundamental biology of idiopathic-type scoliosis has been limited by the lack of a genetic/developmental animal model. Prior to consideration of teleosts, developmental idiopathic-type scoliosis has been considered to be exclusive to humans. Consequently, there is the notion that the syndrome is a result of bipedalism, and many studies try to explain the deformity from this anthrocentric viewpoint. This perspective has been reinforced by the choice of animals used for study, in that chickens and bipedal rats and mice demonstrate idiopathic-type curvature when made melatonin-deficient, but quadrupedal animals do not. Overlooked is the fact that teleosts also demonstrate similar curvature when made melatonin-deficient. Our characterization of the guppy curveback has demonstrated that non-induced idiopathic-type curvature is not exclusive to humans, nor bipedalism. We hypothesize that unique morphological, developmental and genetic parallels between the human and guppy syndromes are due to common molecular pathways involved in the etiopathogenesis of both phenotypes. We explore established gene conservation between human and teleost genomes that are in pathways hypothesized to be involved in the IS syndrome. We present non-induced vertebral wedging as a unique shared feature in IS and curveback that suggests a similar interaction between a molecular phenotype on the level of the vertebral anatomy, and biomechanics. We propose that rather than bipedalism per se , expression of idiopathic-type scoliosis is dependent on normal spinal loading applied along the cranio-caudal axis that interacts with an unknown factor causing the primary curve. In this regard, a comparative biological approach using a simplified teleost model will promote discovery of basic processes integral to idiopathic-type scoliosis in teleosts and humans, and highlight human-specific aspects of the deformity.
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