Advances in Genetics最新文献

With the availability of DNA-based molecular markers during early 1980s and that of sophisticated statistical tools in late 1980s and later, it became possible to identify genomic regions that control a quantitative trait. The two methods used for this purpose included quantitative trait loci (QTL) interval mapping and genome-wide association mapping/studies (GWAS). Both these methods have their own merits and demerits, so that newer approaches were developed in order to deal with the demerits. We have now entered a post-GWAS era, where either the original data on individual genotypes are being used again keeping in view the results of GWAS or else summary statistics obtained through GWAS is subjected to further analysis. The first half of this review briefly deals with the approaches that were used for GWAS, the GWAS results obtained in some major crops (maize, wheat, rice, sorghum and soybean), their utilization for crop improvement and the improvements made to address the limitations of original GWA studies (computational demand, multiple testing and false discovery, rare marker alleles, etc.). These improvements included the development of multi-locus and multi-trait analysis, joint linkage association mapping, etc. Since originally GWA studies were used for mere identification of marker-trait association for marker-assisted selection, the second half of the review is devoted to activities in post-GWAS era, which include different methods that are being used for identification of causal variants and their prioritization (meta-analysis, pathway-based analysis, methylation QTL), functional characterization of candidate signals, gene- and gene-set based association mapping, GWAS using high dimensional data through machine learning, etc. The last section deals with popular resources available for GWAS in plants in the post-GWAS era and the implications of the results of post-GWAS for crop improvement.

Colorectal carcinoma (CRC) is the third most common cancer in men and the second most common cancer in women across the world. Most CRCs occur sporadically, but in 15-35% of cases, hereditary factors are important. Some patients with an inherited predisposition to CRC will be diagnosed with a "genetic polyposis syndrome" such as familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), polymerase proofreading associated polyposis (PPAP), NTHL1-associated polyposis, MSH3-associated polyposis or a hamartomatous polyposis syndrome. Individuals with ≥10 colorectal polyps have traditionally been referred for genetic diagnostic testing to identify APC and MUTYH mutations which cause FAP and MAP respectively. Mutations are found in most patients with >100 adenomas but in only a minority of those with 10-100 adenomas. The reasons that diagnostic laboratories are not identifying pathogenic variants include mutations occurring outside of the open reading frames of genes, individuals exhibiting generalized mosaicism and the involvement of additional genes. It is important to identify patients with an inherited polyposis syndrome, and to define the mutations causing their polyposis, so that the individuals and their relatives can be managed appropriately.

Pre-mRNA splicing, an essential step in eukaryotic gene expression, relies on recognition of short sequences on the primary transcript intron ends and takes place along transcription by RNA polymerase II. Exonic and intronic auxiliary elements may modify the strength of exon definition and intron recognition. Splicing DNA variants (SV) have been associated with human genetic diseases at canonical intron sites, as well as exonic substitutions putatively classified as nonsense, missense or synonymous variants. Their effects on mRNA may be modulated by cryptic splice sites associated to the SV allele, comprehending exon skipping or shortening, and partial or complete intron retention. As splicing mRNA outputs result from combinatorial effects of both intrinsic and extrinsic factors, in vitro functional assays supported by computational analyses are recommended to assist SV pathogenicity assessment for human Mendelian inheritance diseases. The increasing use of next-generating sequencing (NGS) targeting full genomic gene sequence has raised awareness of the relevance of deep intronic SV in genetic diseases and inclusion of pseudo-exons into mRNA. Finally, we take advantage of recent advances in sequencing and computational technologies to analyze alternative splicing in cancer. We explore the Catalog of Somatic Mutations in Cancer (COSMIC) to describe the proportion of splice-site mutations in cis and trans regulatory elements. Genomic data from large cohorts of different cancer types are increasingly available, in addition to repositories of normal and somatic genetic variations. These are likely to bring new insights to understanding the genetic control of alternative splicing by mapping splicing quantitative trait loci in tumors.

The commercial production of high quality natural rubber (NR) solely depends on Hevea brasiliensis Muell. Arg, (Para rubber tree) and accounts for >98% of total production worldwide. NR with its unique properties is an essential commodity for the automobile industry and its synthetic counterparts are in no way substitute to it. The rubber tree genome is very complex and plays an important role in delivering the unique properties of Hevea. But a lack of knowledge on the molecular mechanisms of rubber biosynthesis, disease resistance, etc., in elite clones of rubber still persists. Marker-assisted selection and transgenic techniques were proved to be advantageous in improving the breeding efficiency for latex yield, disease resistance, etc. The suppression subtractive hybridization (SSH), in the form of subtracted cDNA libraries and microarrays, can assist in searching the functions of expressed genes (candidate gene approach). Expressed sequence tags (ESTs) related to various metabolic aspects are well utilized to create EST banks that broadly represent the genes expressed in one tissue, such as latex cells, that assists in the study of gene function and regulation. Transcriptome analysis and gene mapping have been accomplished in Hevea at various stages. However, a selection criterion to delineate high yielding genotypes at the juvenile stage has not been accomplished so far. This is the main pit fall for rubber breeding apart from stock-scion interactions leading to yield differences among a clonally multiplied population. At least four draft genome sequences have been published on Hevea rubber, and all give different genome size and contig lengths-a comprehensive and acceptable genomic map remains unfulfilled. The progress made in molecular markers, latex biosynthesis genes, transcriptome analysis, chloroplast and mitochondrial DNA diversity, paternity identification through Breeding without Breeding (BwB), stimulated latex production and its molecular intricacies, molecular biology of tapping panel dryness, genomics for changed climates and genome mapping are discussed in this review. These information can be utilized to improvise the molecular breeding programs of Hevea in future.

When first published in 1868, Darwin's Pangenesis was almost uniformly rejected by his contemporaries. Until recently it has still been regarded as Darwin's biggest mistake or a brilliant blunder. There are three main reasons for this. First, Galton transfused the blood of one variety of rabbit into another, and then bred together the latter. The results of breeding showed no variations of characters in the offspring. Thus he concluded that Darwin's Pangenesis was incorrect. Second, there was no direct evidence for the existence of Darwin's imaginary gemmules. Third, Darwin's Pangenesis explained the Lamarckian inheritance of acquired characters, graft hybridization, xenia and telegony, which were largely thought to be doubtful phenomena. Now the discoveries of circulating cell-free DNA, mobile RNAs, prions and extracellular vesicles provide striking evidence for the chemical existence of Darwin's supposed gemmules. There is also convincing evidence for heritable changes induced by blood transfusion in which Galton failed to find such effects in his experiment. Moreover, there is increasing evidence for the inheritance of acquired characters, graft hybridization, xenia and other phenomena that Pangenesis was designed to explain. In light of the mounting evidence, it is not proper to continue to consider Pangenesis as Darwin's biggest mistake or a brilliant blunder.

Darwin had many close connections with medical men, and made a number of observations on inherited diseases, clearly describing the inheritance of sex-linked diseases, inherited diseases at corresponding ages, infectious disease and the causes of diseases. Darwin's Pangenesis provides an alternative explanation for cancer metastasis, and is now supported by the discovery of circulating tumour DNA. The "genometastasis hypothesis" proposed by Garcia-Olmo et al. is consistent with Pangenesis. Darwin's view of animal regeneration and his pangenetic explanation is also supported by the recent finding regarding the role of small RNAs and extracellular vesicles in regeneration. There is increasing evidence for genetic information exchange between the donor and recipient cells during transplantation, supporting Darwin's "graft hybridization" concept that gemmules released from the cells of the stock (or scion) could move into the scion (or stock) and incorporated into their cells. In addition, there is also increasing evidence for transposition of the viscera. It appears to me that there is a need to expand the concept of Darwinian medicine by incorporating Darwin's Pangenesis into it.