The individuality of a person: not just genes
Scientists at Stanford University (California) and Yale University (Connecticut), working under the leadership of Professor Michael Snyder, have found that a person's individuality is determined not only by his genes, but also, to a large extent, by the so-called "non-coding" DNA sequences surrounding genes and controlling their work. According to the data obtained, the nature of the interaction of these sequences with proteins belonging to the class of transcription factors varies greatly from person to person and has a pronounced effect on the appearance of a person, his development and even predisposition to certain diseases.
The results of the work done by the authors were published on March 18 in Science Express in the article "Variation in Transcription Factor Binding Among Humans" and on March 17 in the preliminary on-line version of the journal Nature in the article "Genetic analysis of variation in transcription factor binding in yeast".
The variability of coding genes (containing instructions necessary for the synthesis of proteins and RNA) for the entire human population is only 0.025%. Experts have spent decades trying to understand how such minor differences are determined by the infinite variety of human personalities. At the same time, the variability of sequences of non-coding regions of the genome, which make up approximately 98% of all human DNA, ranges from 1-4%. However, until now, scientists could not understand how these regions can contribute to the formation of the human body and personality.
According to Professor Snyder, scientists have done a lot of work to study the differences in gene expression among individuals, but so far no one has paid attention to the differences in the nature of binding transcription factors.
The authors found that the unique changes in the DNA sequences of each person affect the ability of transcription factors to bind to DNA regions that control gene expression. The result of this is a pronounced variability in the expression of nearby genes.
As part of their work, the researchers compared the binding models of transcription factors of 10 people and one chimpanzee. As a result, they identified tens of thousands of binding centers scattered throughout the genome: more than 15,000 for transcription factor NF-kB and more than 19,000 for RNA factor PolII. After that, they analyzed the strength of the interaction of proteins with different binding centers in different individuals.
It turned out that for about 25% of the binding sites of the RNA PolII factor and for 7.5% in NF-kB, the strength of interaction with proteins varies significantly – in some cases, this parameter differs by more than two orders of magnitude in two individuals. (For comparison, the difference in the strength of the interaction of transcription factors and their specific binding centers between humans and chimpanzees averaged 32%.) Many of the identified differences in the strength of interaction are associated with differences in the sequence or structure of binding centers, while some of them showed a pronounced correlation with the level of gene expression. Moreover, it turned out that some of the variable binding centers identified by scientists are located next to genes that provide a person's predisposition to the development of diseases such as type 1 diabetes, systemic lupus erythematosus, leukemia and schizophrenia.
In parallel, the experiments conducted by the researchers on yeast confirmed and expanded the results obtained in the study of human and chimpanzee genomes. In particular, the authors demonstrated that many of the variations in the strength of the interaction of the "transcription factor – binding center" pair and the levels of gene expression are transmitted from generation to generation. They note that using a human or a chimpanzee as an object of research would not allow them to obtain similar results.
The authors of another study, the results of which were also published on March 18 in Science Express in the article "Heritable Individual-Specific and Allele-Specific Chromatin Signatures in Humans", also claim that they were able to identify possible mechanisms by which non-coding regions of DNA determine human phenotypic traits, such as height, eye color or predisposition to diseases.
This group of researchers from the University of Texas at Austin, working under the leadership of Dr. Vishwanath Iyer, has established that certain modifications of chromatin (a complex of DNA and histone proteins that provide dense packaging of genetic material of chromosomes), according to traditional ideas, having an epigenetic – determined by non–genetic factors - nature, in fact, completely depend on from human DNA. Moreover, they demonstrated that these chromatin variations are associated with certain single nucleotide polymorphisms, the so-called "snips" (from the English single nucleotide polymorphism, SNP).
Previously, when conducting genome-wide associative studies, scientists have identified the relationship between snips and certain signs and diseases, but until now it was unclear how snips, often located in non-coding regions of the genome, can determine the phenotypic characteristics of a person. The authors believe that the fact they have identified indicates that the identified chromatin modifications somehow provide the ability of snips to influence the phenotype.
As part of their work, the researchers analyzed two processes involved in controlling the work of genes: a change in the structure of chromatin (straightening a section of the DNA chain is necessary for transcription) and the interaction of DNA and transcription factors. Both of these processes can be regulated epigenetically, that is, through factors such as DNA methylation and histone modifications.
Using high-performance sequencing methods, they analyzed the DNA of six individuals whose genomes were sequenced as part of the 1000 Genomes Project: a family of two parents and a daughter living in Utah, whose ancestors emigrated to the United States from northern and western Europe, and a family of the same composition from Nigeria belonging to the Yoruba people.
As a result, the researchers found that the structure of chromatin varies significantly from individual to individual, and that these variations can be transmitted from generation to generation. In other words, a person inherits from his parents not only genes, but also mechanisms for controlling their work, which contributes to the phenotypic diversity of the human population.
One of the main difficulties faced by specialists trying to apply genetic information to the treatment of diseases is the difficulty of identifying genes whose mutations cause the development of a particular disease. In some cases, whole combinations of genes are involved in the development of the disease. Based on recent data, extensive non-coding regions of the genome also play a role in the formation of predisposition to diseases.
The authors believe that their proposed approach will allow specialists to identify non-coding regions associated with various diseases, which may accelerate the onset of the era of personalized medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru according to the materials:
Stanford University School of Medicine: What makes you unique? Not genes so much as surrounding sequences, says Stanford study;
University of Texas at Austin: Scientists Find More Influences on Inherited Traits;
The Scientist: "Epigenetics" drives phenotype?22.03.2010