CSB349 Lecture 3 Notes

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University of Toronto St. George
Cell and Systems Biology
Alan Moses

CSB349 Lecture 3 – Welcome to the genome II: Genes Slide 2 – What’s really in the (human) genome?  A large proportion of our genome is made up of repetitive elements o Not helpful to us o Function is to make more copies of the repetitive elements in our genome Slide 3 – Where do genes come from?  The major mechanism whereby most of the genes in our genome is created is by gene duplication and divergence o Segmental duplications can duplicate genes  This is a mechanism of gene duplication through retrotransposition o SINEs could hijack the mechanism of replication of LINEs and insert a new copy of themselves into the gene o Our genes can do the same type of thing o Our protein-coding genes can be transcribed into an RNA  RNA can be re-inserted into our genome as a new DNA copy that has been reverse transcribed by the same mechanism as the replication of LINEs and SINEs  The duplication of CSC14B o Top panel  The structure of the ancestral CDC14B gene o Bottom panel  Another copy of CDC14B gene on chromosome 7 that doesn’t have any of the complicated intron and exon structure  It only has one green exon through alternative splicing  The retrogene looks like one of the transcripts of the ancestral gene, but it is a new gene that has been created through retrotransposition Slide 4 – Gene duplication with and without divergence  One gene duplicates through one of the recombination mechanisms or single stranded break repair  This is an example of a tandem duplication of a gene  Genes can duplicate and diverge o Divergence is when the genes change their protein coding sequence and function over evolutionary time  These are the classical fates of duplicated genes o Genes stay similar  duplication without divergence  Two copies of the gene can continue to exist in the genome  This is a rare occurrence o One copy degrades  duplication without divergence  One of the duplicate copies is lost  The most common thing that happens during duplication o One copy acquires a new function (neofunctionalization)  duplication with divergence  One of the genes continues to perform the ancestral function  The second copy can acquire a new function (e.g., through mutations)  This is typical of what we think happens after gene duplication, but not the most prevalent o Genes are subfunctionalized  duplication with divergence  The ancestral gene might have been performing more than one function  The two copies of the gene took on two different functions  The most prevalent Slide 5 – Example of gene duplication and divergence: The globin locus  Why do we need all these different forms of globin?  The functional hemoglobin works as a tetramer o The different hemoglobin that are expressed at different times in the life of an individual are made up of different subunits o The genes encode the different subunits, not the fully functional hemoglobin o The different forms of hemoglobin substitute in different subunits  There used to be a single subunit oxygen carrying molecule o Through gene duplication and divergence, we got the tetrameric complex Slide 6 – Example of gene duplication and divergence: The globin locus  Over time, the relative level of the different subunits is changing  The divergence is the time at which the protein is expressed o Divergence of gene expression  The different forms of hemoglobin have slightly different physiological properties o The fetal hemoglobin has a stronger oxygen binding than the adult hemoglobin Slide 7 – More complicated patterns are also common  This is an example of a whole cluster of genes being duplicated  In different animals, there are increasingly many copies of the Hox gene cluster Slide 8 – More complicated patterns are also common  In different organisms, you can see multiple different patterns of gene presence  The explanation is that there is expression differences  The fish have the most copies of the distal-less gene Slide 9 – Expression of Dlx genes in zebrafish  The different expression of different Dlx genes in the different tissues of the fish  There is a difference of expression in different places in the fish  They are changing their function in terms of where in the body they are expressed Slide 10 – Duplication-degeneration-complementation (DDC) model  Gene duplication and then divergence of gene expression is a type of subfunctionalization o The ancestral function is divided up amongst many copies of the gene o This is a common way that new gene functions arise  This is also called the DDC model  This model describes how genes duplicate and take on different expression patterns by dividing up the ancestral pattern amongst the multiple gene copies Slide 11 – Duplication-degeneration-complementation (DDC) model  The three coloured blocks are mean to represent the regulatory sequences o The arrow indicates the start of transcription o The ancestral gene was expressed in three different places (α, β, δ) o The ancestral gene is required because it’s doing something in three different places  Then there is a gene duplication  Then mutations occur randomly in the regulatory sequences o When a mutation occurs in the green regulatory sequence, then it knocks out expression in the green tissue o Then the other green becomes the only regulatory sequence, which becomes essential so you can’t acquire mutations in it o If random mutations continue, you would end up with a complementary pattern of the preserved regulatory sequence  One of the copies would end up with some of the regulatory sequences, and the other copy would end up with a complementary set of regulatory sequences o This is how the ancestral expression pattern gets partitioned amongst the duplicated genes  Degeneration is the acquisition of mutations in the different regulatory sequences  Complementation is the final pattern where the regulat
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