Evolution of human gene expression

During evolution, biological differences between species can arise not only due to structural differences between genes, but also following changes in how, where and when genes are active. However, we know much less about this second aspect, because large-scale comparative transcriptomics only became feasible relatively recently. In this thesis, I will therefore investigate several aspects of gene expression evolution, with emphasis on our own species. A first step to understanding regulatory evolution is to determine how variation in gene expression is created. Transposable elements (TEs) are genomic parasites that can affect their host genome in a number of ways, including gene expression. In Chapter 2, I investigate to what extent transposable elements (TEs) have contributed to expression differences between humans and chimpanzees. Once expression variation has been established, a combination of selection and drift will decide which variants are passed on to future generations. It is of particular interest to identify changes that were established through positive selection, as these are adaptive. In Chapter 3, I describe a new method to detect positive selection acting on gene expression and apply it to data from humans and chimpanzees. Human gene expression is regulated through several mechanisms associated with transcription and post-transcriptional processing. In Chapter 4, I consider the long-term evolution of the human genome and investigate whether genes have reached their maximum capacity in terms of regulatory complexity. Finally, in Chapter 5, I explore the relationship between gene regulation and sequence conservation by identifying and analysing extremely conserved elements in the genome of the fruit fly Drosophila melanogaster

The evolution of duplicate gene expression in mammalian organs

Gene duplications generate genomic raw material that allows the emergence of novel functions, likely facilitating adaptive evolutionary innovations. However, global assessments of the functional and evolutionary relevance of duplicate genes in mammals were until recently limited by the lack of appropriate comparative data. Here, we report a large-scale study of the expression evolution of DNA-based functional gene duplicates in three major mammalian lineages (placental mammals, marsupials, egg-laying monotremes) and birds, on the basis of RNA sequencing (RNA-seq) data from nine species and eight organs. We observe dynamic changes in tissue expression preference of paralogs with different duplication ages, suggesting differential contribution of paralogs to specific organ functions during vertebrate evolution. Specifically, we show that paralogs that emerged in the common ancestor of bony vertebrates are enriched for genes with brain-specific expression and provide evidence for differential forces underlying the preferential emergence of young testis-and liver-specific expressed genes. Further analyses uncovered that the overall spatial expression profiles of gene families tend to be conserved, with several exceptions of pronounced tissue specificity shifts among lineage-specific gene family expansions. Finally, we trace new lineage-specific genes that may have contributed to the specific biology of mammalian organs, including the little-studied placenta. Overall, our study provides novel and taxonomically broad evidence for the differential contribution of duplicate genes to tissue-specific transcriptomes and for their importance for the phenotypic evolution of vertebrates

Sex-biased microRNA expression in mammals and birds reveals underlying regulatory mechanisms and a role in dosage compensation

Sexual dimorphism depends on sex-biased gene expression, but the contributions of microRNAs (miRNAs) have not been globally assessed. We therefore produced an extensive small RNA sequencing data set to analyze male and female miRNA expression profiles in mouse, opossum, and chicken. Our analyses uncovered numerous cases of somatic sex-biased miRNA expression, with the largest proportion found in the mouse heart and liver. Sex-biased expression is explained by miRNA-specific regulation, including sex-biased chromatin accessibility at promoters, rather than piggybacking of intronic miRNAs on sex-biased protein-coding genes. In mouse, but not opossum and chicken, sex bias is coordinated across tissues such that autosomal testis-biased miRNAs tend to be somatically male-biased, whereas autosomal ovary-biased miRNAs are female-biased, possibly due to broad hormonal control. In chicken, which has a Z/W sex chromosome system, expression output of genes on the Z Chromosome is expected to be male-biased, since there is no global dosage compensation mechanism that restores expression in ZW females after almost all genes on the W Chromosome decayed. Nevertheless, we found that the dominant liver miRNA, miR-122-5p, is Z-linked but expressed in an unbiased manner, due to the unusual retention of a W-linked copy. Another Z-linked miRNA, the male-biased miR-2954-3p, shows conserved preference for dosage-sensitive genes on the Z Chromosome, based on computational and experimental data from chicken and zebra finch, and acts to equalize male-to-female expression ratios of its targets. Unexpectedly, our findings thus establish miRNA regulation as a novel gene-specific dosage compensation mechanism

A Selection Index for Gene Expression Evolution and Its Application to the Divergence between Humans and Chimpanzees

The importance of gene regulation in animal evolution is a matter of long-standing interest, but measuring the impact of selection on gene expression has proven a challenge. Here, we propose a selection index of gene expression as a straightforward method for assessing the mode and strength of selection operating on gene expression levels. The index is based on the widely used McDonald-Kreitman test and requires the estimation of four quantities: the within-species and between-species expression variances as well as the sequence heterozygosity and divergence of neutrally evolving sequences. We apply the method to data from human and chimpanzee lymphoblastoid cell lines and show that gene expression is in general under strong stabilizing selection. We also demonstrate how the same framework can be used to estimate the proportion of adaptive gene expression evolution

Germ Cell-Specific Targeting of DICER or DGCR8 Reveals a Novel Role for Endo-siRNAs in the Progression of Mammalian Spermatogenesis and Male Fertility

Small non-coding RNAs act as critical regulators of gene expression and are essential for male germ cell development and spermatogenesis. Previously, we showed that germ cell-specific inactivation of Dicer1, an endonuclease essential for the biogenesis of micro-RNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), led to complete male infertility due to alterations in meiotic progression, increased spermatocyte apoptosis and defects in the maturation of spermatozoa. To dissect the distinct physiological roles of miRNAs and endo-siRNAs in spermatogenesis, we compared the testicular phenotype of mice with Dicer1 or Dgcr8 depletion in male germ cells. Dgcr8 mutant mice, which have a defective miRNA pathway while retaining an intact endo-siRNA pathway, were also infertile and displayed similar defects, although less severe, to Dicer1 mutant mice. These included cumulative defects in meiotic and haploid phases of spermatogenesis, resulting in oligo-, terato-, and azoospermia. In addition, we found by RNA sequencing of purified spermatocytes that inactivation of Dicer1 and the resulting absence of miRNAs affected the fine tuning of protein-coding gene expression by increasing low level gene expression. Overall, these results emphasize the essential role of miRNAs in the progression of spermatogenesis, but also indicate a role for endo-siRNAs in this process

Populariserad yta och vetenskapligt djup. Översättning av dubbelbottnade uttryck i en bok om evolutionsbiologi

Den här uppsatsen tar sin utgångspunkt i en översättning av andra kapitlet ur den populärvetenskapliga boken Dinner with Darwin av Jonathan Silvertown. Uppsatsen inleds med en källtextanalys och en redogörelse för den globala strategi som har använts vid översättningen. Därefter följer en översättningsanalys som behandlar översättningen av ett för källtexten typiskt pedagogiskt grepp som här benämns ”dubbelbottnade uttryck”. Dessa definieras som bildspråk, ordlekar och andra konstruktioner som har dels en allmän betydelse, dels en textspecifik betydelse som bygger på källtextens vetenskapliga innehåll. Genom tre exempel belyses olika lokala strategier för att överföra dubbelbottnade uttryck till svenska utan att deras funktion som pedagogiska och textstrukturerande element går förlorad. I uppsatsens sista del diskuteras hur de valda strategierna visar på skillnader mellan populärvetenskaplig och skönlitterär översättning

Trollkarlarna från Oz. Källtexttrogenhet och läsbarhet i fyra svenska versioner av en barnboksklassiker

I den här uppsatsen presenteras en undersökning av tre översättningar och en moderniserad bearbetning av den amerikanska barnboksklassikern Trollkarlen från Oz av L. Frank Baum. Syftet har varit att studera hur de fyra måltextversionerna skiljer sig åt i fråga om läsbarhet och källtexttrogenhet. För att studera läsbarheten användes ett antal kvantitativa textmått för att mäta texternas språkliga uppbyggnad och ordvariation medan källtexttrogenheten mättes med hjälp av en ny metod som kontrasterar substantivanvändningen i källtext och måltext. Analysen visade att det inte fanns några stora språkliga skillnader som kunde knytas till läsbarhet, men att texterna däremot var mycket olika när det gällde innehållslig källtext- trogenhet. Bland översättningarna var det förstaöversättningen som låg längst ifrån käll- texten, vilket stämmer överens med den s.k. nyöversättningshypotesen. De största avstegen från källtexten fanns dock som väntat i den moderniserade bearbetningen, och dessa visade sig bidra till ökad läsbarhet, bl.a. genom förekomsten av expliciteringar och förtydligande tillägg. Sammantaget visade analysen att vissa aspekter av läsbarheten hade förbättrats på bekostnad av källtexttrogenheten, men att det inte fanns något samband mellan källtext- trogenhet och läsbarhet i rent språklig bemärkelse för de fyra svenska måltextversionerna av Trollkarlen från Oz

Nested ANOVA estimates of variance components based on datasets with unequal variances.

<p><i>V_b</i> is the between-species variance, <i>V_wh</i> the human within-species variance, <i>V_eh</i> the human error variance, <i>V_wc</i> the chimpanzee within-species variance and <i>V_ec</i> is the chimpanzee error variance. The variance estimates were averaged across 10000 simulations. The true variances used to generate the data are given in brackets. The first set of simulations was based on the average observed variances in humans and chimpanzee, and the chimpanzee error variance and within-species variances were then increased by a factor of 10.</p

Tree illustrating the time between the most recent common ancestors of each species (<i>t_b</i>), the expected time to coalescence for two randomly chosen lineages within a given species (<i>t_w</i>) and the difference between <i>t_w</i> and the time at which all lineages coalesce (<i>t_c</i>).

<p>Tree illustrating the time between the most recent common ancestors of each species (<i>t_b</i>), the expected time to coalescence for two randomly chosen lineages within a given species (<i>t_w</i>) and the difference between <i>t_w</i> and the time at which all lineages coalesce (<i>t_c</i>).</p

Estimates of the selection index for individual genes under different evolutionary scenarios, assuming that all measurements are without error and can be obtained from an infinite number of individuals.

<p>A. Genes with true SI = −2 (negative selection) in red, genes with true SI = 0 (neutral evolution) in green and genes with true SI = 2 (positive selection) in blue. B. Genes with true SI = −5 in red, true SI = 0 in green and true SI = 5 in blue.</p