PM-149 Lecture 4: Eukaryotic Chromosomes & Genome Organisation 2024-2025 PDF

Eukaryotic chromosomes & Genome Organisation  Learning objectives Understand how DNA exists in the cell How form can affect function. Appreciation and understanding that there are different types of DNA sequences. The importance of genomics The Structure of Euk...

Eukaryotic chromosomes & Genome Organisation  Learning objectives Understand how DNA exists in the cell How form can affect function. Appreciation and understanding that there are different types of DNA sequences. The importance of genomics The Structure of Eukaryotic Chromatin DNA + protein = Chromatin Eukaryote genome packaging A nucleosome structure  Distribution of heterochromatin and euchromatin in the nucleus Chromatin changes during cell cycle Heterochrom atin: highly condensed nucleoprotein Euchromatin: less condensed nucleoprotein Click this link to watch an animation of how DNA is packaged Genome organisation The Human Genome Project (1990 – 2003)  Types of DNA sequences in the human genome Sequencing the human genome showed - Most of the genome is comprised of repetitive DNA (~60%) Sequences present in multiple copies ~44% of the entire genome is composed of TEs Regulatory role – determining which genes are switched on and when.  Transposons in maize Barbara McClintock 1902-1992 Coloured and variegated Nobel Laureate 1983 maize kernels Her discovery was met with scepticism and virtually discounted Fig. 20.11, Transposon effects on corn kernel color. Interacting genetic loci –Ds and Ac Retrotranspos DNA on transposon  Impact of TEs in Humans Genome Evolution Reshuffling of genes and regulatory sequences Genomic Instability Extensive source of mutations Duplications Alterations in Gene Expression Cancer Alcoholism Psychiatric conditions  Repetitive DNA Repeated sequences of DNA that occur in multiple copies throughout the genome. Tandemly repetitive Interspersed repetitive Copy number variants (CNVs) - repeated sequences in the genome that vary between individuals Two main groups (short and long tandem repeats) Common CNV - tri-nucleotide repeat (STR)  Huntington’s Disease: caused by tandem CAG repeats Unaffected individuals have 27-36 CAG repeats For affected individuals: CAG Repeat Median Age of Onset (years) Size 39 66 40 59 41 54 42 49 43 44 44 42 45 37 46 36 47 33 48 32 49 28 50 27 https://www.bbc.co.uk/news/health-50425039 Tandem repeats are also used by forensic geneticists Repeats 2-5 nts long are called STR Each individual has 2 alleles per STR each with a specific number of repeats  This photo shows Earl Washington just before his release in 2001, after 17 years in prison. Source of STR STR STR sample marker 1 marker 2 marker 3 Semen on victim 17, 19 13, 16 12, 12 Earl Washington 16, 18 14, 15 11, 12 Kenneth Tinsley 17, 19 13, 16 12, 12 These and other STR data exonerated Washington and led Tinsley to plead guilty to the murder.  Telomeres (TTAGGG repeats) They protect the ends of our chromosomes by forming a cap DNA replication shortens the chromosomes by 25-200 bases per replication. When the telomere becomes too short, the chromosome reaches a ‘critical length’ and can no longer be replicated. This critical length triggers senescence End replication problem  mtDNA – Mutations & Disease Over 100 pathogenic point mutations Over 200 deletions/insertions and rearrangements Deafness Diabetes Cardiomyopathy Blindness Dementia Exercise intolerance The genomics era  Relevance of Genomics in Medicine Genetic variations arise through mutation Characterising mutations is fundamental to understanding the genetics of human diseases Due to limitations in technology mutation identification has been limited NGS has allowed novel and uncharacterised variants to be identified  The Reference Genome “a complete human genome” Helps identify differences between individuals Allows identification of disease- causing genes Revolutionised forensics and human evolution Current reference – only 20 individuals Does not reflect global genomic diversity The Diagnostic Odyssey