BOIS 412/812: Human Genetics—A Peer Review of Teaching Project Benchmark Portfolio

This portfolio focuses on Human Genetics, an upper-division course taken primarily by biology majors to fulfill elective credit in their degree. This course studies the genetic basis for human variation, with the goal of placing this variation in the context of human evolutionary history and the consequences of this variation for medical understanding and treatments. In Human Genetics, students complete an original synthetic research paper on a human genetic disorder. Through writing this paper, students are expected to learn how to navigate electronic databases and online resources on human genetic diseases, and to read and synthesize the primary scientific literature. This portfolio describes the teaching methods used to guide students through this process. The information and concepts to be taught in Human Genetics are expected to be useful for students going on to do research in a biological field, for those intending to pursue medical and health-related professions, and in general in producing informed and critical citizens who are empowered to make scientifically sound decisions

Heterochromatin and genetic conflict

Meiosis is a dangerous business. The two alleles in diploid organisms share an evolutionary interest in the survival and reproduction of their host individual; however, as soon as they segregate into haploid gametes, these alleles find themselves competing for transmission to the next generation (1). In males, the development of all four meiotic products into functional gametes fosters the evolution of alleles that disrupt the development or viability of gametes carrying the alternate allele. Systems that distort Mendelian segregation (hence, segregation distorters) typically comprise at least two loci: a trans-acting drive locus (such as a gene that encodes a poison) that targets alleles that are sensitive to the poison at a second, linked locus (2). A major impediment to the evolution of segregation distorters is the requirement that the poisonous allele be tightly linked to resistant alleles at the target locus; otherwise, distorters will commit suicide when paired with a sensitive allele (3). As a result, segregation distorters on autosomes are invariably associated with inversions that suppress recombination between the distorter and target loci. In contrast, heteromorphic sex chromosomes, where the Y chromosome is highly degenerated, can facilitate the evolution of segregation distorters because the X and Y frequently share little homologous sequence and do not recombine along most or all of their length. Thus, sex-chromosome segregation distorters that distort the sex ratio of the progeny of males that carry them (hence, sex-ratio distorters) are predicted to evolve frequently (4). The presence of sex-ratio distorters in populations selects for resistant Y chromosomes and autosomal suppressors that restore male fertility and a balanced sex ratio, and may lead to either balanced polymorphisms or open-ended arms races between loci that function in the male germ line (5). A recent study in PNAS has identified a gene required for sex-ratio distortion in Drosophila simulans (6), providing novel insight into the genetic and molecular mechanisms used by these selfish elements and their effects on genome evolution and species formation

BOIS 412/812: Human Genetics—A Peer Review of Teaching Project Benchmark Portfolio

This portfolio focuses on Human Genetics, an upper-division course taken primarily by biology majors to fulfill elective credit in their degree. This course studies the genetic basis for human variation, with the goal of placing this variation in the context of human evolutionary history and the consequences of this variation for medical understanding and treatments. In Human Genetics, students complete an original synthetic research paper on a human genetic disorder. Through writing this paper, students are expected to learn how to navigate electronic databases and online resources on human genetic diseases, and to read and synthesize the primary scientific literature. This portfolio describes the teaching methods used to guide students through this process. The information and concepts to be taught in Human Genetics are expected to be useful for students going on to do research in a biological field, for those intending to pursue medical and health-related professions, and in general in producing informed and critical citizens who are empowered to make scientifically sound decisions

Genetic conflict and sex chromosome evolution

Chromosomal sex determination systems create the opportunity for the evolution of selfish genetic elements that increase the transmission of one sex chromosome at the expense of its homolog. Because such selfish elements on sex chromosomes can reduce fertility and distort the sex ratio of progeny, unlinked suppressors are expected to evolve, bringing different regions of the genome into conflict over the meiotic transmission of the sex chromosomes. Here we argue that recurrent genetic conflict over sex chromosome transmission is an important evolutionary force that has shaped a wide range of seemingly disparate phenomena including the epigenetic regulation of genes expressed in the germline, the distribution of genes in the genome, and the evolution of hybrid sterility between species

Genetic Factors Affecting Hybrid Male Sterility Leading to Speciation

The process whereby speciation occurs can come about through the evolution of barriers to gene flow. One of these barriers to gene flow can be an incompatibility, which leaves hybrids dead or sterile. Two theories underlie the work of this experiment, Haldane’s Rule and the large X effect. Haldane’s Rule is the observation that unisexual inviability or sterility among species’ hybrids is almost always found in the heterogametic sex. The large X effect is the observation that substitution of one species’ X-chromosome for another’s has a disproportionately large effect on hybrid fitness compared to similar substitution of an autosome. For Drosophila, the cause of the large X effect has been identified as density dependent for the number of sterility-inducing incompatibilities on the Xchromosome. In this project we are using Drosophila simulans and Drosophila mauritiana. We are using introgressed lines of flies that make use of physical markers that can be used to track the progress of genetic material throughout crosses. The visible markers that we are using affect eye color and express fluorescent protein, allowing us to determine the regions on the recombinant chromosomes that contain the factors leading to hybrid male sterility. Males that carry the recombinant X-chromosomes are sterile unless the sterility factors have been removed via recombination. Flies that are fertile will be genotyped using Real-Time PCR. Genetic mapping will then allow us to determine the location of the sterility-causing gene in question. At this time we have generated a number of recombinant genotypes and through the genotyping of these samples we have narrowed our candidate region. At the start of this project the region was approximately 300kb in length and we have shortened that segment of interest to 100kb. By shortening this segment we have narrowed our search area for this sterility-causing gene that is of interest to us

Little Evidence for Demasculinization of the \u3ci\u3eDrosophila X\u3c/i\u3e Chromosome among Genes Expressed in the Male Germline

Male-biased genes—those expressed at higher levels in males than in females—are underrepresented on the X chromosome of Drosophila melanogaster. Several evolutionary models have been posited to explain this so-called demasculinization of the X. Here, we show that the apparent paucity of male-biased genes on the X chromosome is attributable to global X-autosome differences in expression in Drosophila testes, owing to a lack of sex chromosome dosage compensation in the male germline, but not to any difference in the density of testis-specific or testis-biased genes on the X chromosome. First,using genome-wide gene expression data from 20 tissues,we find no evidence that genes with testis-specific expression are underrepresented on the X chromosome. Second, using contrasts in gene expression profiles among pairs of tissues,we recover a statistical under representation of testis-biased genes on the X but find that the pattern largely disappears once we account for the lack of dosage compensation in the Drosophila male germline. Third, we find that computationally “demasculinizing” the autosomes is not sufficient to produce an expression profile similar to that of the X chromosome in the testes. Our findings thus show that the lack of sex chromosome dosage compensation in Drosophila testes can explain the apparent signal of demasculinization on the X, whereas evolutionary demasculinization of the X cannot explain its overall reduced expression in the testes

RNAi Doxxes Segregation Distorters on the X

Species with chromosomal sex determination are susceptible to an evolutionary tug-of-war over sex chromosome segregation. RNA silencing has been proposed to play a role in this intragenomic conflict. Reporting in Developmental Cell, Lin et al. (2018) demonstrate that RNA interference is key to this conflict as a genome defender. ... This work from Lin et al. (2018) provides exciting new evidence that RNA silencing may play a special role as a genome defense against native genes gone rogue. It will be interesting to see how these evolutionary games mediated by RNA silencing influence germline evolution and the dynamics of speciation

Invasion of the P elements: Tolerance is not futile

Organisms are locked in an eternal struggle with parasitic DNA sequences that live inside their genomes and wreak havoc on their host’s chromosomes as they spread through populations. To combat these parasites, host species have evolved elaborate mechanisms of resistance that suppress their activity. A new study in Drosophila indicates that, prior to the acquisition of resistance, individuals can vary in their ability to tolerate the activity of these genomic parasites, ignoring or repairing the damage they induce. This tolerance results from variation at genes involved in germline development and DNA damage checkpoints and suggests that these highly conserved cellular processes may be influenced by current and historical intragenomic parasite loads

Invasion of the P elements: Tolerance is not futile

Organisms are locked in an eternal struggle with parasitic DNA sequences that live inside their genomes and wreak havoc on their host’s chromosomes as they spread through populations. To combat these parasites, host species have evolved elaborate mechanisms of resistance that suppress their activity. A new study in Drosophila indicates that, prior to the acquisition of resistance, individuals can vary in their ability to tolerate the activity of these genomic parasites, ignoring or repairing the damage they induce. This tolerance results from variation at genes involved in germline development and DNA damage checkpoints and suggests that these highly conserved cellular processes may be influenced by current and historical intragenomic parasite loads

Mitochondrial Dysfunction and Infection Generate Immunity–Fecundity Tradeoffs in \u3ci\u3eDrosophila\u3c/i\u3e

Physiological responses to short-term environmental stressors, such as infection, can have long-term consequences for fitness, particularly if the responses are inappropriate or nutrient resources are limited. Genetic variation affecting energy acquisition, storage, and usage can limit cellular energy availability and may influence resourceallocation tradeoffs even when environmental nutrients are plentiful. Here, we utilized Drosophila mitochondrial– nuclear genotypes to test whether disrupted mitochondrial function interferes with nutrient-sensing pathways, and whether this disruption has consequences for tradeoffs between immunity and fecundity. We found that an energetically-compromised genotype was relatively resistant to rapamycin—a drug that targets nutrient-sensing pathways and mimics resource limitation. Dietary resource limitation decreased survival of energetically-compromised flies. Furthermore, survival of infection with a natural pathogen was decreased in this genotype, and females of this genotype experienced immunity–fecundity tradeoffs that were not evident in genotypic controls with normal energy metabolism. Together, these results suggest that this genotype may have little excess energetic capacity and fewer cellular nutrients, even when environmental nutrients are not limiting. Genetic variation in energy metabolism may therefore act to limit the resources available for allocation to life-history traits in ways that generate tradeoffs even when environmental resources are not limiting