Medical Genetics Lecture 7 PDF

Medical Genetics TOPICS & REFERENCES The role of gene duplication in evolution. PAGE 185 Copy number variants (CNVs). PAGE 185 Inversions. PAGE 186 Consequences of inversions during gamete formation. PAGE 186 Evolutionary advantages of inversions. PAGE 187 The role of gene d...

Medical Genetics TOPICS & REFERENCES The role of gene duplication in evolution. PAGE 185 Copy number variants (CNVs). PAGE 185 Inversions. PAGE 186 Consequences of inversions during gamete formation. PAGE 186 Evolutionary advantages of inversions. PAGE 187 The role of gene duplication in evolution During the study of evolution, it is intriguing to speculate on the possible mechanisms of genetic variation. The origin of unique gene products present in more recently evolved organisms but absent in ancestral forms is a topic of particular interest. In other words, how do “new” genes arise? The process of gene duplication is hypothesized to be the major source of new genes, as proposed in 1970 by Susumu Ohno in his provocative monograph, Evolution by Gene Duplication. Ohno’s thesis is based on the supposition that the products of many genes, present as only a single copy in the genome, are indispensable to the survival of members of any species during evolution. Therefore, unique genes are not free to accumulate mutations sufficient to alter their primary function and give rise to new genes. Copy number variants (CNVs). As we entered the era of genomics and became capable of sequencing entire genomes, it was quickly realized that duplications of large DNA sequences, most often involving thousands of base pairs, occur on a regular basis. When individuals in the same species are compared, the number of copies of any given sequence is found to vary—sometimes there are larger numbers, and in other cases, copies have been deleted, resulting in smaller numbers. These variations, because they represent quantitative differences in the number of DNA sequences, are termed copy number variations (CNVs) and are found in both coding and noncoding regions of the genome CNVs are of major interest in genetics because they are now believed to play crucial roles in the expression of many of our individual traits, in both normal and diseased individuals. Currently, when CNVs of sizes ranging from 50 bp to 3 Mb are considered, it is estimated that they occupy between 5–10 percent of the human genome. Current studies have focused on finding associations with human diseases. CNVs appear to have both positive and negative associations with many diseases in which the genetic basis is not yet fully understood. For example, pathogenic CNVs have been associated with autism and other neurological disorders, and with cancer. Additionally, CNVs are suspected to be associated with Type I diabetes and cardiovascular disease.  Inversions The inversion, another class of structural variation, is a type of chromosomal aberration in which a segment of a chromosome is turned around 180 degrees within a chromosome. An inversion does not involve a loss of genetic information but simply rearranges the linear gene sequence. An inversion requires breaks at two points along the length of the chromosome and subsequent reinsertion of the inverted segment. By forming a chromosomal loop prior to breakage, the newly created “sticky ends” are brought close together and rejoined. The inverted segment may be short or quite long and may or may not include the centromere. If the centromere is not part of the rearranged chromosome segment, it is a paracentric inversion. If the centromere is part of the inverted segment, it is described as a pericentric inversion. Although inversions appear to have a minimal impact on the individuals bearing them, their consequences are of great interest to geneticists. Organisms that are heterozygous for inversions may produce aberrant gametes that have a major impact on their offspring.  Consequences of inversions during gamete formation  If only one member of a homologous pair of chromosomes has an inverted segment, normal linear synapsis during meiosis is not possible. Organisms with one inverted chromosome and one noninverted homolog are called inversion heterozygotes. Two such chromosomes in meiosis can be paired only if they form an inversion loop  If crossing over does not occur within the inverted segment of the inversion loop, the homologs will segregate, which results in two normal and two inverted chromatids that are distributed into gametes. However, if crossing over does occur within the inversion loop, abnormal chromatids are produced.  In any meiotic tetrad, a single crossover between nonsister chromatids produces two parental chromatids and two recombinant chromatids. When the crossover occurs within a paracentric inversion, however, one recombinant dicentric chromatid (two centromeres) and one recombinant acentric chromatid (lacking a centromere) are produced. Both contain duplications and deletions of chromosome segments as well. During anaphase, an acentric chromatid moves randomly to one pole or the other or may be lost, while a dicentric chromatid is pulled in two directions. This polarized movement produces dicentric bridges that are cytologically recognizable. A dicentric chromatid usually breaks at some point so that part of the chromatid goes into one gamete and part into another gamete during the reduction divisions. Therefore, gametes containing either recombinant chromatid are deficient in genetic material. When such a gamete participates in fertilization, the zygote most often develops abnormally, if at all. Consequences of inversions during gamete formation  A similar chromosomal imbalance is produced as a result of a crossover event between a chromatid bearing a pericentric inversion and its noninverted homolog. The recombinant chromatids that are directly involved in the exchange have duplications and deletions. In plants, gametes receiving such aberrant chromatids fail to develop normally, leading to aborted pollen or ovules. Thus, lethality occurs prior to fertilization, and inviable seeds result. In animals, the gametes have developed prior to the meiotic error, so fertilization is more likely to occur in spite of the chromosome error. However, the end result is the production of inviable embryos following fertilization. In both cases, viability is reduced.  Because offspring bearing crossover gametes are inviable and not recovered, it appears as if the inversion suppresses crossing over. Actually, in inversion heterozygotes, the inversion has the effect of suppressing the recovery of crossover products when chromosome exchange occurs within the inverted region. If crossing over always occurred within a paracentric or pericentric inversion, 50 percent of the gametes would be ineffective. The viability of the resulting zygotes is therefore greatly diminished. Furthermore, up to one-half of the viable gametes have the inverted chromosome, and the inversion will be perpetuated within the species. The cycle will be repeated continuously during meiosis in future generations. Evolutionary advantages of inversions Because recovery of crossover products is suppressed in inversion heterozygotes, groups of specific alleles at adjacent loci within inversions may be preserved from generation to generation. If the alleles of the involved genes confer a survival advantage on organisms maintaining them, the inversion is beneficial to the evolutionary survival of the species. For example, if a set of alleles ABcDef is more adaptive than sets AbCdeF or abcdEF, effective gametes will contain this favorable set of genes, undisrupted by crossing over. In laboratory studies, the same principle is applied using balancer chromosomes, which contain inversions. When an organism is heterozygous for a balancer chromosome, desired sequences of alleles are preserved during experimental work. Edwards syndrome (trisomy 18) Findings: Prominent occiput, Rocker-bottom feet, Intellectual disability, Nondisjunction, Clenched fists with overlapping fingers, low-set Ears, Micrognathia (small jaw), congenital heart disease, omphalocele, myelomeningocele. Patau syndrome (trisomy 13) Findings: severe intellectual disability, rockerbottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart (pump) disease, polycystic kidney disease, omphalocele. Death usually occurs by age 1.