Mario Cáceres

Elevated gene expression levels distinguish human from non-human primate brains

Little is known about how the human brain differs from that of our closest relatives. To investigate the genetic basis of human specializations in brain organization and cognition, we compared gene expression profiles for the cerebral cortex of humans, chimpanzees, and rhesus macaques by using several independent techniques. We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup. Surprisingly, most differences between the brains of humans and non-human primates involved up-regulation, with ≈90% of the genes being more highly expressed in humans. By contrast, in the comparison of human and chimpanzee heart and liver, the numbers of up- and down-regulated genes were nearly identical. Our results indicate that the human brain displays a distinctive pattern of gene expression relative to non-human primates, with higher expression levels for many genes belonging to a wide variety of functional classes. The increased expression of these genes could provide the basis for extensive modifications of cerebral physiology and function in humans and suggests that the human brain is characterized by elevated levels of neuronal activity.

Human brain evolution: insights from microarrays.

Several recent microarray studies have compared gene-expression patterns n humans, chimpanzees and other non-human primates to identify evolutionary changes that contribute to the distinctive cognitive and behavioural characteristics of humans. These studies support the surprising conclusion that the evolution of the human brain involved an upregulation of gene expression relative to non-human primates, a finding that could be relevant to understanding human cerebral physiology and function. These results show how genetic and genomic methods can shed light on the basis of human neural and cognitive specializations, and have important implications for neuroscience, anthropology and medicine.

RATES OF DIVERGENCE IN GENE EXPRESSION PROFILES OF PRIMATES, MICE, AND FLIES: STABILIZING SELECTION AND VARIABILITY AMONG FUNCTIONAL CATEGORIES

Abstract The extent to which natural selection shapes phenotypic variation has long been a matter of debate among those studying organic evolution. We studied the patterns of gene expression polymorphism and divergence in several datasets that ranged from comparisons between two very closely related laboratory strains of mice to comparisons across a considerably longer time scale, such as between humans and chimpanzees, two species of mice, and two species of Drosophila. The results were analyzed and interpreted in view of neutral models of phenotypic evolution. Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels. Nevertheless, the range of rates of divergence is large with highly significant differences in the rate and patterns of transcription divergence across functional classes defined on the basis of the gene ontology annotation (primates and mice datasets) or on the basis of the pattern of sex‐biased gene expression (Drosophila). Moreover, rates of divergence of sex‐biased genes in the contrast between Drosophila species show a distinct pattern from that observed in the contrast between populations of D. melanogaster. Hence, we discuss the time scale of the changes observed and its consequences for the relationship between variation in gene expression within and between species. Finally, we argue that differences in mRNA levels of the magnitudes observed herein could be explained by a remarkably small number of generations of directional selection.

The Chromosomal Polymorphism Linked to Variation in Social Behavior in the White-Throated Sparrow (Zonotrichia albicollis) Is a Complex Rearrangement and Suppressor of Recombination

Variation in social behavior and plumage in the white-throated sparrow (Zonotrichia albicollis) is linked to an inversion polymorphism on chromosome 2. Here we report the results of our comparative cytogenetic mapping efforts and population genetics studies focused on the genomic characterization of this balanced chromosomal polymorphism. Comparative chromosome painting and cytogenetic mapping of 15 zebra finch BAC clones to the standard (ZAL2) and alternative (ZAL2m) arrangements revealed that this chromosome is orthologous to chicken chromosome 3, and that at a minimum, ZAL2 and ZAL2m differ by a pair of included pericentric inversions that we estimate span at least 98 Mb. Population-based sequencing and genotyping of multiple loci demonstrated that ZAL2m suppresses recombination in the heterokaryotype and is evolving as a rare nonrecombining autosomal segment of the genome. In addition, we estimate that the first inversion within the ZAL2m arrangement originated 2.2 ± 0.3 million years ago. Finally, while previously recognized as a genetic model for the evolution of social behavior, we found that the ZAL2/ZAL2m polymorphism also shares genetic and phenotypic features with the mouse t complex and we further suggest that the ZAL2/ZAL2m polymorphism is a heretofore unrecognized model for the early stages of sex chromosome evolution.

Brain response to traumatic brain injury in wild-type and interleukin-6 knockout mice: a microarray analysis

Traumatic injury to the brain is one of the leading causes of injury‐related death or disability. Brain response to injury is orchestrated by cytokines, such as interleukin (IL)‐6, but the full repertoire of responses involved is not well known. We here report the results obtained with microarrays in wild‐type and IL‐6 knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8 and 16 days post‐lesion. Overall gene expression was analyzed by using Affymetrix genechips/oligonucleotide arrays with ∼12 400 probe sets corresponding to ∼10 000 different murine genes (MG_U74Av2). A robust, conventional statistical method (two‐way anova) was employed to select the genes significantly affected. An orderly pattern of gene responses was clearly detected, with genes being up‐ or down‐regulated at specific timings consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma. IL‐6 deficiency showed a dramatic effect in the expression of many genes, especially in the 1 day post‐lesion timing, which presumably underlies the poor capacity of IL‐6 knockout mice to cope with brain damage. The results highlight the importance of IL‐6 controlling the response of the brain to injury as well as the suitability of microarrays for identifying specific targets worthy of further study.

Novel roles for metallothionein‐I + II (MT‐I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: Insights from global gene expression profiling in wild‐type and MT‐I + II knockout mice

Traumatic injury to the brain is one of the leading causes of injury‐related death or disability, especially among young people. Inflammatory processes and oxidative stress likely underlie much of the damage elicited by injury, but the full repertoire of responses involved is not well known. A genomic approach, such as the use of microarrays, provides much insight in this regard, especially if combined with the use of gene‐targeted animals. We report here the results of one of these studies comparing wild‐type and metallothionein‐I + II knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8, and 16 days postlesion (dpl) using Affymetrix genechips/oligonucleotide arrays interrogating ∼10,000 different murine genes (MG_U74Av2). Hierarchical clustering analysis of these genes readily shows an orderly pattern of gene responses at specific times consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma, as well as a prominent effect of MT‐I + II deficiency. The results thoroughly confirmed the importance of the antioxidant proteins MT‐I + II in the response of the brain to injury and opened new avenues that were confirmed by immunohistochemistry. Data in KO, MT‐I‐overexpressing, and MT‐II‐injected mice strongly suggest a role of these proteins in postlesional activation of neural stem cells.

A Common 16p11.2 Inversion Underlies the Joint Susceptibility to Asthma and Obesity

The prevalence of asthma and obesity is increasing worldwide, and obesity is a well-documented risk factor for asthma. The mechanisms underlying this association and parallel time trends remain largely unknown but genetic factors may be involved. Here, we report on a common ~0.45 Mb genomic inversion at 16p11.2 that can be accurately genotyped via SNP array data. We show that the inversion allele protects against the joint occurrence of asthma and obesity in five large independent studies (combined sample size of 317 cases and 543 controls drawn from a total of 5,809 samples; combined OR = 0.48, p = 5.5 × 10(-6)). Allele frequencies show remarkable worldwide population stratification, ranging from 10% in East Africa to 49% in Northern Europe, consistent with discordant and extreme genetic drifts or adaptive selections after human migration out of Africa. Inversion alleles strongly correlate with expression levels of neighboring genes, especially TUFM (p = 3.0 × 10(-40)) that encodes a mitochondrial protein regulator of energy balance and inhibitor of type 1 interferon, and other candidates for asthma (IL27) and obesity (APOB48R and SH2B1). Therefore, by affecting gene expression, the ~0.45 Mb 16p11.2 inversion provides a genetic basis for the joint susceptibility to asthma and obesity, with a population attributable risk of 39.7%. Differential mitochondrial function and basal energy balance of inversion alleles might also underlie the potential selection signature that led to their uneven distribution in world populations.

Identification of Copy Number Variants Defining Genomic Differences among Major Human Groups

Background Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations. Methodology/Principal Findings We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH) in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level. Conclusions Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

A recurrent inversion on the eutherian X chromosome

Chromosomal inversions have an important role in evolution, and an increasing number of inversion polymorphisms are being identified in the human population. The evolutionary history of these inversions and the mechanisms by which they arise are therefore of significant interest. Previously, a polymorphic inversion on human chromosome Xq28 that includes the FLNA and EMD loci was discovered and hypothesized to have been the result of nonallelic homologous recombination (NAHR) between near-identical inverted duplications flanking this region. Here, we carried out an in-depth study of the orthologous region in 27 additional eutherians and report that this inversion is not specific to humans, but has occurred independently and repeatedly at least 10 times in multiple eutherian lineages. Moreover, inverted duplications flank the FLNA–EMD region in all 16 species for which high-quality sequence assemblies are available. Based on detailed sequence analyses, we propose a model in which the observed inverted duplications originated from a common duplication event that predates the eutherian radiation. Subsequent gene conversion homogenized the duplications, thereby providing a continuous substrate for NAHR that led to the recurrent inversion of this segment of the genome. These results provide an extreme example in support of the evolutionary breakpoint reusage hypothesis and point out that some near-identical human segmental duplications may, in fact, have originated >100 million years ago.

InvFEST, a database integrating information of polymorphic inversions in the human genome

The newest genomic advances have uncovered an unprecedented degree of structural variation throughout genomes, with great amounts of data accumulating rapidly. Here we introduce InvFEST (http://invfestdb.uab.cat), a database combining multiple sources of information to generate a complete catalogue of non-redundant human polymorphic inversions. Due to the complexity of this type of changes and the underlying high false-positive discovery rate, it is necessary to integrate all the available data to get a reliable estimate of the real number of inversions. InvFEST automatically merges predictions into different inversions, refines the breakpoint locations, and finds associations with genes and segmental duplications. In addition, it includes data on experimental validation, population frequency, functional effects and evolutionary history. All this information is readily accessible through a complete and user-friendly web report for each inversion. In its current version, InvFEST combines information from 34 different studies and contains 1092 candidate inversions, which are categorized based on internal scores and manual curation. Therefore, InvFEST aims to represent the most reliable set of human inversions and become a central repository to share information, guide future studies and contribute to the analysis of the functional and evolutionary impact of inversions on the human genome.