Evolutionary and Population Genomics
Summary: Fyodor Kondrashov uses a combination of computational and experimental approaches to study the evolution of genes and genomes.
All forms of life, including our own species, are constrained by their genetic and evolutionary origin. These constraints on the phenotype of the organism are apparent, as are restrictions on the future directions of evolution. For example, our ancient and recent evolutionary history places great constraints on our well-being by predisposing us to various diseases. If our evolutionary history were different, the predisposition to disease would also be different. Understanding the process of evolution can thus provide important information on the reasons behind the existing constraints in all life forms, including those that may be restricting our own well-being.
Evolution of different life forms occurs through the interplay of three main factors: mutation, selection, and random population dynamics (called genetic drift). All aspects of life that we see around us today emerged because of the interplay of these three factors. An understanding of their action helps us understand the capabilities and limitations of all living organisms. One of the fundamental directions of my research is concerned with measuring and modeling the rate of mutation, the strength of selection, and the degree of genetic drift in different life forms. I study these parameters at the level of genome sequences, including the sequence of genes and their location in genomes.
Among the areas of genome evolution I study are the evolution of genes and genome organization. I am particularly interested in the role of selection on the origin and maintenance of gene copies. My previous work suggested that the appearance of an extra gene copy in the genome has selective consequences. My hypothesis is that an extra copy of a gene can lead to a higher dose of a gene product, which in many cases can be deleterious, although occasionally an extra gene copy may be beneficial. Current research suggests that copy-number variations play a wide role in different human diseases and that mutations that copy whole genes are, on average, unlikely to be entirely neutral.
My past work also suggested that many new gene copies that are maintained in genomes were preferred by natural selection and probably led to organisms that are better adapted to variable environmental conditions. In the next few years I will gather data from many recent gene duplications in model organisms that will allow me to test this hypothesis. Unraveling the role of selection in the emergence of gene copies can lead to novel approaches in bioengineering and to a better understanding of the mechanisms of gene dosage regulation in human disease.
I am also concerned with a higher order of interaction of the factors of mutation, selection, and genetic drift in evolution and how different constraints limit the evolutionary process. The assortment of different life forms creates a false impression that the evolutionary process can solve any problem and create any phenotype through natural selection. However, two factors severely restrict what natural selection can create. First, natural selection cannot provide solutions that violate basic laws of physics. Second, the action of natural selection maintains high fitness at all times and must reject all deleterious variants, which constitute a vast majority of all possible genetic changes. Thus, if the shortest path to an adaptation is blocked by the deleterious state of intermediate genetic steps, natural selection may be powerless to create this adaptation.
What molecular factors make a mutation deleterious? On a superficial level, a mutation is deleterious if it disrupts something important, such as a protein-coding gene or its regulation. However, as we have discovered in the past, many mutations that are damaging in our genetic background are benign in another. In other words, the deleterious impact of one mutation can be fixed by another mutation. My laboratory is studying the codependence of the impact of mutations and fitness. Some mutations appear to cancel out their deleterious effects because they affect amino acids that are directly interacting in the same protein. It is possible that amino acids interacting between different molecules also have the same effects; however, no direct evidence for this mechanism has been found yet. Indirect interactions of mutations—for example, those that affect genes in the same metabolic pathway—are also yet to be investigated in detail.
In the next few years I expect to advance our understanding of the phenomena of individually deleterious but mutually benign mutations. My work will be concerned with how the mutations interact on the molecular level and how interactions between mutations affect the evolution of genes and genomes.
This work was supported in part by a Plan Nacional Grant from the Spanish Ministry of Science and Innovation.
As of January 17, 2012