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Evolution at the Molecular Level Outline Evolution of genomes Based on DNA alterations and selection Genomes grow in size by repeated duplications, which can arise by recombination and transposition Duplication, diversification, and selection results in genome evolution Genetic drift, selection, duplication of exons, globin gene family: an example of molecular evolution Earliest cells evolved into three kingdoms of living organisms Archaea and bacteria now contain no introns Introns late evolutionary elaboration Fig. 21.3 Basic body plans of some Burgess shale organisms Many species resulting from metazoan explosion have disappeared Fig. 21.4 Evolution of humans 35 mya – primates 6 mya – humans diverged from chimpanzees Fig. 21.5 Evolution of Humans Human and chimpanzee genomes 99% similar Karyotypes almost same No significant difference in gene function Divergence may be due to a few thousand isolated genetic changes not yet identified Probably regulatory sequences DNA alterations form the basis of genomic evolution Mutations arise in several ways Replacement of individual nucleotides Deletions / Insertions: 1bp to several Mb Single base substitutions Missense mutations: replace one amino acid codon with another Nonsense mutations: replace amino acid codon with stop codon Splice site mutations: create or remove exon-intron boundaries Frameshift mutations: alter the ORF due to base substitutions Dynamic mutations: changes in the length of tandem repeat elements Effect of mutations on population Neutral mutations are unaffected by agents of selection Deleterious mutations will disappear from a population by selection against the allele Rare mutations increase fitness Genomes grow in size through repeated duplications Some duplications result from transposition Other duplications arise from unequal crossing over during recombination Transposable elements move from place to place in the genome 1930s Marcus Rhoades and 1950s Barbara McClintock – transposable elements in corn 1983 Nobel Prize - McClintock Found in all organisms Most 50 – 10,000 bp May be present hundreds of times in a genome TEs can generate mutations in adjacent genes http://www.dnaftb.org/dnaftb/32/concept/index.html Common mechanism of transposition Catalysed by transposases Regulation of transposase expression controls transposition Catalytic domain of transposase involved in transphosphorylation step that initiates DNA cleavage & strand transfer. Common mechanism of transposition 2 sequential steps Site specific cleavage of DNA at the end of TE Complex of transposase-element ends brought to DNA target where strand transfer is carried out by covalent joining of 3’end of TE to target DNA Transposons are now classified into 5 families On the basis of their transposase proteins 1) 2) 3) 4) 5) DDE-transposases RT/En transposases (reverse transcriptase/endonuclease) Tyrosine (Y) transposases Serine (S) transposases Rolling circle (RC) or Y2 transposases Nature Rev Mol. Cell Biol (Nov2003) 4(11):865-77) Recombination Homologous recombination exchange between homologous DNA sequences; accomplished by a set of enzymes function: meiosis I of eukaryotic cell division, double-strand break repair, telomere maintenance replication is an integral part of the reaction, allowing reformation of functional replication forks after any fork blocking event Genetic drift and mutations can turn duplications into pseudogenes Diversification of a duplicated gene followed by selection can produce a new gene Genome size increases through duplication of exons, genes, gene families and entire genomes Fig. 21.10 Basic structure of a gene Fig. 21.11 Exon duplication Genes may elongate by exon duplication to generate tandem exons that determine tandem functional domains e.g. antibody molecule Fig. 21.12a Exon shuffling may give rise to new genes e.g., tissue plasminogen activator (TPA) Fig. 21.12b Duplications of entire genes can create multigene families Fig. 21.13a Unequal crossing over can expand and contract gene numbers in multigene families Fig. 21.13b Intergenic gene conversion can increase variation among members of a multigene family One gene is changed, the other is not Fig. 21.14a Concerted evolution can lead to gene homogeneity Fig. 21.15 Unequal crossing over Gene conversion Evolution of gene superfamilies Large set of genes divisible into smaller sets, or families Genes in each family more closely rated to each other than to other members of the family Arise by duplication and divergence Evolution of globin superfamily Fig. 21.16 Organisation of globin genes Fig. 21.16 Developmental variation in gene expression a-like chains - z & a b-like chains - e, g, d, b Fig. 21.16 Adult human made of a2b2 – 97%; a2d2 - ~2%; a2g2-~1% (fetal persistence) Gene expression controlled by location Fig. 21.16 e – embryonic yolk sac g – yolk sac & fetal liver b & d – adult bone marrow Evolution of mouse globin superfamily Fig. 21.16 Evolution of mouse globin superfamily Fig. 21.16 The Haemoglobinopathies Thalassemias -Anaemias associated with impaired synthesis of Hb subunits Thalassaemias can arise from different mutations causing a disease of varying severity. a0/b0 thalassaemias – globin chain absent a+/b+ thalassaemias – normal globin chain in reduced amounts a- thalassemias a- thalassemias deletion of one or both a globins in an a gene cluster Severity depends on whether the individual has 1,2,3, or 4 missing a globin genes. GENOTYPE a+ a+ a+a+ a+a a+a+ PHENOTYPE Normal Silent carrier a+ a a-thalassaemia trait minor anaemic conditions HbH Hydrops foetalis mild – moderate anaemia foetus survives until around birth a+a a+a+ a a a+a aa aa aa asymptomatic condition. a-thalassaemia – 2 b- thalassemias b- thalassemias 5’ Mutations in b globin cluster are of different types gene deletion transcriptional mutation RNA processing mutations RNA cleavage signal mutations Nonsense & frameshift mutations 3’ Non coding regulatory regions Exons Introns (InterVening Sequences) 3’ cleavage mutant deletion RNA splicing mutant transcription mutant nonsense mutation frameshift insertion frameshift deletion b- thalassemias Main genetic mechanisms that contribute to the phenotypic diversity of the b-thalassaemias.