Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Analysis of Development Edited by Prof Benjamin H Willier, Prof Paul A Weiss and Prof Viktor Hamburger Pp xii + 735 (Philadelphia and London: W B Saunders Company, 1955) 105s

Mechanisms of Development

Transposable elements are mobile genetic units that exhibit broad diversity in their structure and transposition mechanisms. Transposable elements occupy a large fraction of many eukaryotic genomes and their movement and accumulation represent a major force shaping the genes and genomes of almost all organisms. This review focuses on DNA-mediated or class 2 transposons and emphasizes how this class of elements is distinguished from other types of mobile elements in terms of their structure, amplification dynamics, and genomic effect. We provide an up-to-date outlook on the diversity and taxonomic distribution of all major types of DNA transposons in eukaryotes, including Helitrons and Mavericks. We discuss some of the evolutionary forces that influence their maintenance and diversification in various genomic environments. Finally, we highlight how the distinctive biological features of DNA transposons have contributed to shape genome architecture and led to the emergence of genetic innovations in different eukaryotic lineages.

/pdf/dna-transposons-and-the-evolution-of-eukaryotic-genomes-4rq0mdhrsc.pdf

DNA Transposons and the Evolution of Eukaryotic Genomes

Variation in DNA content has been largely ignored as a factor in evolution, particularly following the advent of sequence-based approaches to genomic analysis. The significant genome size diversity among organisms (more than 200 000-fold among eukaryotes) bears no relationship to organismal complexity and both the origins and reasons for the clearly non-random distribution of this variation remain unclear. Several theories have been proposed to explain this ‘C-value enigma’ (heretofore known as the ‘C-value paradox’), each of which can be described as either a ‘mutation pressure’ or ‘optimal DNA’ theory. Mutation pressure theories consider the large portion of non-coding DNA in eukaryotic genomes as either ‘junk’ or ‘selfish’ DNA and are important primarily in considerations of the origin of secondary DNA. Optimal DNA theories differ from mutation pressure theories by emphasizing the strong link between DNA content and cell and nuclear volumes. While mutation pressure theories generally explain this association with cell size as coincidental, the nucleoskeletal theory proposes a coevolutionary interaction between nuclear and cell volume, with DNA content adjusted adaptively following shifts in cell size. Each of these approaches to the C-value enigma is problematic for a variety of reasons and the preponderance of the available evidence instead favours the nucleotypic theory which postulates a causal link between bulk DNA amount and cell volume. Under this view, variation in DNA content is under direct selection via its impacts on cellular and organismal parameters. Until now, no satisfactory mechanism has been presented to explain this nucleotypic effect. However, recent advances in the study of cell cycle regulation suggest a possible ‘gene–nucleus interaction model’ which may account for it. The present article provides a detailed review of the debate surrounding the C-value enigma, the various theories proposed to explain it, and the evidence in favour of a causal connection between DNA content and cell size. In addition, a new model of nucleotypic influence is developed, along with suggestions for further empirical investigation. Finally, some evolutionary implications of genome size diversity are considered, and a broadening of the traditional ‘biological hierarchy’ is recommended.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-185X.2000.tb00059.x

Coincidence, coevolution, or causation? DNA content, cell size, and the C-value enigma.

Increasing evidence indicates widespread occurrence of pharmaceuticals and personal care products (PPCPs) in municipal effluent discharges and surface waters. Studies that characterize the fate and effects of PPCPs in aquatic systems are limited, and to our knowledge, data regarding pharmaceutical accumulation in fish of effluent-dominated ecosystems have not been previously reported. In the present study, fish populations were sampled from a reference stream and an effluent-dominated stream in north Texas, USA. Lepomis macrochirus, Ictalurus punctatus, Cyprinus carpio, and Pomoxis nigromaculatus were killed; the liver, brain, and lateral filet tissues dissected; and the tissues stored at -80 degrees C until analysis. Fish tissues were extracted using solid-phase extraction and then analyzed by gas chromatography-mass spectrometry in the negative chemical ionization mode. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and the SSRI metabolites norfluoxetine and desmethylsertraline were detected at levels greater than 0.1 ng/g in all tissues examined from fish residing in a municipal effluent-dominated stream. To our knowledge, the present study is the first report of SSRI residues in fish residing within municipal effluent-dominated systems.

Determination of select antidepressants in fish from an effluent-dominated stream.

HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology.

https://www.mdpi.com/1422-0067/21/2/654/pdf

HMGA Genes and Proteins in Development and Evolution.

Localization and gene expression of serotonin1A (5HT1A) receptors in human brain postmortem

European water frog hybrids Rana esculenta (R. ridibundaxR. lessonae) reproduce hemiclonally, by hybridogenesis: in the germ line they exclude the genome of one parental species and produce haploid gametes with an unrecombined genome of the other parental species. In the widespread L-E population system, both sexes of hybrids (E) coexist with R. lessonae (L). They exclude the lessonae genome and produce ridibunda gametes. In the R-E system, hybrid males coexist with R. ridibunda (R); they exclude either their ridibunda or their lessonae genome and produce sperm with a lessonae or with a ridibunda genome or a mixture of both kinds of sperm. We examined 13 male offspring, 12 of which were from crosses between L-E system and R-E system frogs. All were somatically hybrid. With one exception, they excluded the lessonae genome in the germ line and subsequently endoreduplicated the ridibunda genome. Spermatogonial metaphases contained a haploid or a diploid number of ridibunda chromosomes, identified through in situ hybridization to a satellite DNA marker, and by spermatocyte I metaphases containing a haploid number of ridibunda bivalents. The exception, an F1 hybrid between L-E system R. lessonae and R-E system R. ridibunda, was not hybridogenetic, showed no genome exclusion, and evidenced a disturbed gametogenesis resulting from the combination of two heterospecific genomes. None of the hybridogenetic hybrids showed any cell lines excluding the ridibunda genome, the pattern most frequent in hybrids of the R-E system, unique to that system, and essential for its persistence. A particular combination of R-E system lessonae and R-E system ridibunda genomes seems necessary to induce the R-E system type of hemiclonal gametogenesis.

https://www.zora.uzh.ch/id/eprint/390/1/12076_Ragghianti_Gen_Res_2007.pdf

Gametogenesis of intergroup hybrids of hemiclonal frogs

We have studied a family of long repetitive DNA sequences (Hsr1) interspersed in the large genome of the European plethodontid salamanderHydromantes. The sequence analysis of a 5-kb fragment (Hsr1A) of one member has revealed significant similarities with aminoacidic domains of retroviruses and retrotransposons. The similarity of the reverse transcriptase domain and the gene organization identifies Hsr1A as a member of thegypsy/Ty3 class of retrotransposons. We hypothesize that Hsr1 sequences are vestiges of an invasion of theHydromantes genome that occurred early in the evolutionary history of these European plethodontids. About 106 Hsr1 sequences are present in the largeHydromantes genome. This is the highest number of copies so far discovered for retrotransposon-like elements in eukaryote organisms.

Gypsy-Ty3 like elements in the genome of the terrestrial salamander Hydromantes (Amphibia: Urodela)

We have characterized a highly repetitive family, named Hy/Pol III, in the genome of the European salamanders Hydromantes (Plethodontidae). This family consists of short, tandemly repeated sequences organized in clusters, scattered through the genome as shown both by in situ hybridization to chromosomes and by Southern blot hybridization. The repeat unit is about 200 bp in length and it is a composite element since it contains a SINE-like retroposon with a tRNA structure, flanked by two short direct repeats. The whole element itself is bordered by two other direct repeats. The sequence data suggest that two elements, presumably derived from polymerase III transcripts, have been inserted one into the other, giving rise to the observed composite structure. During evolution the Hy/Pol III family was then amplified by tandem duplication at the DNA level. The inferred relationships between Hy/Pol III members from three representative species of the European Hydromantes suggests that a subfamily structure characterizes the evolutionary history of this family.

Silvia Marracci

Papers

HMGA Genes and Proteins in Development and Evolution.

Localization and gene expression of serotonin1A (5HT1A) receptors in human brain postmortem

Gametogenesis of intergroup hybrids of hemiclonal frogs

Gypsy-Ty3 like elements in the genome of the terrestrial salamander Hydromantes (Amphibia: Urodela)

A tandemly repeated dna family originated from sine-related elements in the european plethodontid salamanders (amphibia, urodela)