Tandem chimerism as a means to increase protein complexity in the human genome.

The "one-gene, one-protein" rule, coined by Beadle and Tatum, has been fundamental to molecular biology. The rule implies that the genetic complexity of an organism depends essentially on its gene number. The discovery, however, that alternative gene splicing and transcription are widespread phenomena dramatically altered our understanding of the genetic complexity of higher eukaryotic organisms; in these, a limited number of genes may potentially encode a much larger number of proteins. Here we investigate yet another phenomenon that may contribute to generate additional protein diversity. Indeed, by relying on both computational and experimental analysis, we estimate that at least 4%-5% of the tandem gene pairs in the human genome can be eventually transcribed into a single RNA sequence encoding a putative chimeric protein. While the functional significance of most of these chimeric transcripts remains to be determined, we provide strong evidence that this phenomenon does not correspond to mere technical artifacts and that it is a common mechanism with the potential of generating hundreds of additional proteins in the human genome.

The complex organization of human cognitive domains and their heritability: a systematic review

Una revisión sistemática de la organización compleja de los dominios cognitivos humanos y su heredabilidad. Antecedentes: se ha propuesto que la estructura de la cognición humana respondería a un sistema jerárquico, donde las secuencias propias a una acción se organizarían desde sub-unidades de análisis hasta funciones de nivel superior relativamente complejas. Esta estructura organizacional estaría reflejada en las representaciones neurales que subyacen al comportamiento humano, así como también en sus sustratos genéticos. El objetivo del presente estudio fue explorar la posible organización jerárquica de las influencias genéticas subyacentes a los dominios cognitivos humanos. Método: se revisaron treinta y cuatro estudios de la heredabilidad de la cognición en muestras de la población general, que incluyeron medidas de inteligencia, habilidades verbales y manipulativas, memoria, memoria de trabajo y velocidad de procesamiento. Resultados: diversos dominios cognitivos mostraron distintas proporciones de influencias genéticas, con las mayores estimaciones de heredabilidad halladas para las funciones cognitivas de nivel superior y las menores estimaciones para las funciones de orden medio o inferior. Conclusiones: tomando como referencia los conocimientos actuales acerca del neurodesarrollo humano, las contribuciones genéticas de las habilidades cognitivas parecen organizarse paralelamente al crecimiento ontogénico del cerebro. Se discuten estos resultados en relación a la interacción entre el control genético de las funciones cognitivas y sus influencias ambientales.

Variability of the nucleolar organizer activity in human lymphocytes via Ag-staining.

Chromosomes with Ag staining that varies from one metaphase to the other can be distinguished from those with an Ag-staining that is the same in all metaphases. The intercellular variation of an Ag-NOR can be attributed to many different factors. Whatever the importance of technical factors, they do not seem to account for the large variations in Ag-staining which were observed for each ac. This suggests the existence of a natural intercellular variability of the NOR's activity. The variation of the Ag-stainability of a given NOR, the diversity of Ag-stainings observed on the ten ac of one individual and the differences that exist between individuals raise the question of the existence of a compensation of activity between nucleolar organizers. The study, for each individual, of the mean sum of staining per metaphase reveals that this value is not absolutely constant from one individual to another; in the carriers of Robertsonian fusions it is smaller than in chromosomally normal individuals. The analysis of the transmission shows that inactive NORs remain inactive and that active NORs present a variation in the activity from one generation to the next.

Lack of support for the association between facial shape and aggression: a reappraisal based on a worldwide population genetics perspective

Antisocial and criminal behaviors are multifactorial traits whose interpretation relies on multiple disciplines. Since these interpretations may have social, moral and legal implications, a constant review of the evidence is necessary before any scientific claim is considered as truth. A recent study proposed that men with wider faces relative to facial height (fWHR) are more likely to develop unethical behaviour mediated by a psychological sense of power. This research was based on reports suggesting that sexual dimorphism and selection would be responsible for a correlation between fWHR and aggression. Here we show that 4,960 individuals from 94 modern human populations belonging to a vast array of genetic and cultural contexts do not display significant amounts of fWHR sexual dimorphism. Further analyses using populations with associated ethnographical records as well as samples of male prisoners of the Mexico City Federal Penitentiary condemned by crimes of variable level of inter-personal aggression (homicide, robbery, and minor faults) did not show significant evidence, suggesting that populations/individuals with higher levels of bellicosity, aggressive behaviour, or power-mediated behaviour display greater fWHR. Finally, a regression analysis of fWHR on individual"s fitness showed no significant correlation between this facial trait and reproductive success. Overall, our results suggest that facial attributes are poor predictors of aggressive behaviour, or at least, that sexual selection was weak enough to leave a signal on patterns of between- and within-sex and population facial variation.

Directional dominance on stature and cognition in diverse human populations.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Controlling complexity: the clinical relevance of mouse complex genetics.

Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches.

Host Genetics of Response to Hepatitis B Vaccine: A Systematic Review

Background. Hepatitis B virus (HBV) is an important cause of chronic viral disease worldwide and can be life threatening. While a safe and effective vaccine is widely available, 5 to 10% of healthy vaccinees fail to achieve a protective anti-hepatitis B surface antigen antibody (anti-HBs) titer (>10mIU/ml). A limited number of studies investigated host genetics of the response to HBV vaccine. To our knowledge, no comprehensive overview of genetic polymorphisms both within and outside the HLA system has been done so far. Aim. The aim of this study was to perform a systematic review of the literature of human genetics influencing immune response after hepatitis B vaccination. Methods. Literature searches using keywords were conducted in the electronic databases Medline, Embase and ISI Web of Science the cut-off date being March 2014. After selection of papers according to stringent inclusion criteria, relevant information was systematically collected from the remaining articles, including demographic data, number of patients, schedule and type of vaccine, phenotypes, genes and single nucleotide polymorphisms (SNPs) genotyping results and their association with immune response to hepatitis B vaccine. Results. The literature search produced a total of 1968 articles from which 46 studies were kept for further analyses. From these studies, data was extracted for 19 alleles from the human leukocyte antigen (HLA) region that were reported as significant at least twice. Among those alleles, 9 were firmly associated with vaccine response outcome (DQ2 [DQB1*02 and DQB1*0201], DR3 [DRB1*03 and DRB1*0301], DR7 [DRB1*07 and DRB1*0701], C4AQ0, DPB1*0401, DQ3, DQB1*06, DRB1*01 and DRB1*13 [DRB1*1301]). In addition, data was extracted for 55 different genes from which 13 extra-HLA genes had polymorphisms that were studied by different group of investigators or by the same group with a replication study. Among the 13 genes allowing comparison, 4 genes (IL-1B, IL-2, IL-4R and IL- 6) revealed no significant data, 6 genes (IL-4, IL-10, IL-12B, IL-13, TNFA, IFNG and TLR2) were explored with inconsistent results and 2 genes (CD3Z and ITGAL) yielded promising results as their association with vaccine response was confirmed by a replication approach. Furthermore, this review produced a list of 46 SNPs from 26 genes that were associated with immune response to vaccine only once, providing novel candidates to be tested in datasets from existing genome-wide association studies (GWAS). Conclusion. To the best of our knowledge, this is the first systematic review of immunogenetic studies of response to hepatitis B vaccine. While this work reassesses the role of several HLA alleles on vaccine response outcome, the associations with polymorphisms in genes outside the HLA region were rather inconsistent. Moreover, this work produced a list of 46 significant SNPs that were reported by a single group of investigators, opening up some interesting possibilities for further research.

Decay of linkage disequilibrium within genes across HGDP-CEPH human samples: most population isolates do not show increased LD

Background It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8. Results Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates. Conclusion The 'isolated population' label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.

Genetics of amyotrophic lateral sclerosis

La sclérose latérale amyotrophique (SLA) est la maladie des neurones moteurs la plus fréquente, affectant 4-6 individus par 100,000 habitants à l’échelle mondiale. La maladie se caractérise par une faiblesse et une atrophie musculaire suite à la dégénérescence des neurones du cortex moteur, tronc cérébral et moelle épinière. Les personnes atteintes développent les premiers symptômes à l’âge adulte et la maladie progresse sur une période de trois à cinq ans. Il a été répertorié qu’environ 10% des patients ont une histoire familiale de SLA; 90% des gens affectés le sont donc de façon sporadique. La découverte il y a 19 ans de mutations dans le gène zinc/copper superoxide dismutase (SOD1), présentes dans 15-20% des cas familiaux de SLA et environ 2% du total des individus affectés, a été l’événement déclencheur pour la découverte de variations génétiques responsables de la maladie. La recherche sur la génétique de la SLA a connu une progression rapide ces quatre dernières années avec l’identification de mutations dans de nouveaux gènes. Toutefois, même si certains de ces gènes ont été démontrés comme réellement liés à la maladie, la contribution d’autres gènes demeure incertaine puisque les résultats publiés de ceux-ci n’ont pas, à ce jour, été répliqués. Une portion substantielle de cas reste cependant à être génétiquement expliquée, et aucun traitement à ce jour n’a été démontré comme étant efficace pour remédier, atténuer ou prévenir la maladie. Le but du projet de recherche de doctorat était d’identifier de nouveaux gènes mutés dans la SLA, tout en évaluant la contribution de gènes nouvellement identifiés chez une importante cohorte multiethnique de cas familiaux et sporadiques. Les résultats présentés sont organisés en trois sections différentes. Dans un premier temps, la contribution de mutations présentes dans le gène FUS est évaluée chez les patients familiaux, sporadiques et juvéniles de SLA. Précisément, de nouvelles mutations sont rapportées et la proportion de mutations retrouvées chez les cas familiaux et sporadiques de SLA est évaluée. De plus, une nouvelle mutation est rapportée dans un cas juvénile de SLA; cette étude de cas est discutée. Dans un deuxième temps, de nouvelles avenues génétiques sont explorées concernant le gène SOD1. En effet, une nouvelle mutation complexe est rapportée chez une famille française de SLA. De plus, la possibilité qu’une mutation présente dans un autre gène impliqué dans la SLA ait un impact sur l’épissage du gène SOD1 est évaluée. Finalement, la dernière section explique la contribution de nouveaux gènes candidats chez les patients atteints de SLA. Spécifiquement, le rôle des gènes OPTN, SIGMAR1 et SORT1 dans le phénotype de SLA est évalué. Il est souhaité que nos résultats combinés avec les récents développements en génétique et biologie moléculaire permettent une meilleure compréhension du mécanisme pathologique responsable de cette terrible maladie tout en guidant le déploiement de thérapies suite à l’identification des cibles appropriées.

Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene

Acheiropodia is an autosomal recessive developmental disorder presenting with bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. This severely handicapping condition appears to affect only the extremities, with no other systemic manifestations reported. Recently, a locus for acheiropodia was mapped on chromosome 7q36. Herein we report the narrowing of the critical region for the acheiropodia gene and the subsequent identification of a common mutation in C7orf2-the human orthologue of the mouse Lmbr1 gene-that is responsible for the disease. Analysis of five families with acheiropodia, by means of 15 polymorphic markers, narrowed the critical region to 1.3 cM, on the basis of identity by descent, and to <0.5 Mb, on the basis of physical mapping. Analysis of C7orf2, the human orthologue of the mouse Lmbr1 gene, identified a deletion in all five families, thus identifying a common acheiropodia mutation. The deletion was identified at both the genomic-DNA and mRNA level. It leads to the production of a C7orf2 transcript lacking exon 4 and introduces a premature stop codon downstream of exon 3. Given the nature of the acheiropodia phenotype, it appears likely that the Lmbr1 gene plays an important role in limb development.

Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

Because GABA(A) receptors containing alpha 2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha 2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine`s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of alpha 2-GABA(A) receptors (alpha 2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In alpha 2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha 2-GABA(A) receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

Gene duplication: a drive for phenotypic diversity and cause of human disease

Gene duplication is one of the key factors driving genetic innovation, i.e., producing novel genetic variants. Although the contribution of whole-genome and segmental duplications to phenotypic diversity across species is widely appreciated, the phenotypic spectrum and potential pathogenicity of small-scale duplications in individual genomes are less well explored. This review discusses the nature of small-scale duplications and the phenotypes produced by such duplications. Phenotypic variation and disease phenotypes induced by duplications are more diverse and widespread than previously anticipated, and duplications are a major class of disease-related genomic variation. Pathogenic duplications particularly involve dosage-sensitive genes with both similar and dissimilar over- and underexpression phenotypes, and genes encoding proteins with a propensity to aggregate. Phenotypes related to human-specific copy number variation in genes regulating environmental responses and immunity are increasingly recognized. Small genomic duplications containing defense-related genes also contribute to complex common phenotypes.

Mapping and cloning of genes from portions of the human genome using somatic cell hybrids

Human x rodent somatic cell hybrids have played an important role in human genetics research. They have been especially useful for assigning genes to chromosomes and isolating DNA markers from specific regions of the human genome.^ By employing a combination of somatic cell genetic, recombinant DNA, and cytogenetic techniques, human DNA excision repair gene ERCC4 was mapped regionally to human 16p13.13-13.2, even though the gene has not been cloned. Human x Chinese hamster ovary (CHO) cell hybrids selected for human ERCC4 activity and containing 16p13.1-p13.3 as the only human genetic material were identified. These hybrids were used to order DNA markers located in 16p13.1-p13.3. New DNA markers physically close to ERCC4 were isolated from such hybrids. Using amplified human DNA from the hybrids as probe in fluorescent in situ hybridization, the short arm breakpoint in the chromosome 16 inversion associated with acute myelomonocytic leukemia (AMML) was found to be physically close to the ERCC4 gene. The physical mapping and eventually, the cloning of the ERCC4 gene, will benefit the understanding of the DNA repair system and the study of other important biomedical problems such as tumorigenesis.^ To facilitate the cloning of ERCC4 gene and, in general, the cloning of genes from any defined regions of the human genome, a method was developed for the direct isolation of human transcribed genes ffom somatic cell hybrids. cDNA was prepared from human x rodent hybrid by using consensus 5$\sp\prime$ splice site sequences as primers. These primers were designed to select immature, unspliced messenger RNA (still retaining species specific repeat sequences) as templates. Screening of a derived cDNA library for human repeat sequences resulted in the isolation of human clones at the anticipated frequency with characteristics expected of exons of transcribed human genes. The usefulness of the splice site specific primers was analyzed and the cDNA synthesis conditions with these primers were optimized. The procedure was shown to be sensitive enough to clone weakly expressed genes. Studying the expression of the represented genes with the isolated clones was shown to be feasible. Such regional specific human gene fragments will be very valuable for many human genetic studies such as the search of inherited disease genes and the construction of a cDNA map of the human genome. ^

How is the Human Genome Project doing, and what have we learned so far?

In this paper, we describe the accomplishments of the initial phase of the Human Genome Project, with particular attention to the progress made toward achieving the defined goals for constructing genetic and physical maps of the human genome and determining the sequence of human DNA, identifying the complete set of human genes, and analyzing the need for adequate policies for using the information about human genetics in ways that maximize the benefits for individuals and society.