YR1 Lecture - Genetics 3 Mutations and pedigrees 2024 PDF

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COPYRIGHT COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of University of Western Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. 1 Gene$cs 3 Muta%ons and pedigrees Dr. Elizabeth O’Connor [email protected] Learning objectives Describe how errors during meiosis can lead to chromosomal abnormalities Explain how different types of mutations affect the RNA and/or protein produced by the gene Interpret a pedigree and identify the meaning of the lines and symbols 3 Lecture overview Chromosomal copy number mutations Gene level mutations – types and description Mutational effects on reading frames Introduction to pedigrees 4 Genes and chromosomes Every cell has 23 pairs of chromosomes - 22 pairs of autosomes and 2 sex chromosomes - Sex chromosomes are XX (female) or XY (male) 5 Chromosome structure Chromosomes have a short arm p, and a long arm q The centromere is where spindle fibres attach during cell division (p) The bands that can be seen upon G staining are numbered Eg. 13p12.2 = chromosome 13 short arm p (q) region 1 band 2 sub band 2 6 Chromosomal rearrangements Alteration in the copy number of a complete set of chromosomes OR Alteration in the structure of an individual chromosome(s) Suffix “ploid” is the number of sets of chromosomes in a cell Haploid – single set (N)(gametes via meiosis) Diploid – normal set (2N), 2 of each chromosome Triploid – full additional set of each chromosome (3N) 7 Chromosomal rearrangements Polyploid = > diploid; rare in humans, common in plants - seen in cancer cells and adult liver cells and megakaryocytes Aneuploid – variation in individual chromosome number - seen in humans - eg. Trisomy 21 (Down syndrome) Suffix “somy” is the number of an individual chromosome in aneuploids Rearrangements that alter the structure of individual chromosomes - Duplications - Inversions - Deletions - Translocations 8 Whole chromosome changes 9 Revision of meiosis Meiosis I DNA replication Homologous chromosomes pair along equator and recombine Daughter cells contain 1n chromosomes (haploid) Meiosis II Each daughter cell from meiosis I divides again, separating sister chromatids 10 Nondisjunction during meiosis 11 Aneuploidy in humans Many changes to individual chromosome copy number are nonviable - leads to miscarriage (20-60% ferXlisaXons depending on maternal age) Trisomy 13 and 18 can be viable to birth but 90% death by 1 year Trisomy 21 – Down syndrome, near-normal life expectancy but many deleterious effects Monosomy X (XO) – Turner syndrome, shorter life expectancy due to deleterious effects, inferXle XXY – Klinefelter’s syndrome, near-normal life expectancy fewer deleterious effects, feminised male, inferXle XYY – Jacobs syndrome – few effects, normal life expectancy ferXle Trisomy X (XXX) – few effects, normal life expectancy, ferXle Child with Down syndrome12 Partial chromosome changes 13 Crossing over in meiosis Occurs in Metaphase I of meiosis Exchange of genetic material between a pair of chromosomes Designed to increase genetic variation Susceptible to mutation events (unequal crossing over, misalignment) Thought to be ~30-40 new germline mutations from your parents; ~1-2 lethal recessive 14 Duplications and deletions Original chromosome Original chromosome Rearranged chromosome Rearranged chromosome Gene loss of segregaXon ability -> loss of chromosome Can -> monoallelic expression of recessive genes Can -> haploinsufficiency – of a gene that requires 2 gene products for normal funcXon Variation in genome-wide mutation rates within and between human families; Nature Genetics 43: 712–714 (2011) 15 Inversions Doesn’t change gene dosage, unless the breakpoint disrupts genes Makes meiosis during gamete producXon tricky though… The post-meiosis deleXon product chromosomes are oden nonviable due to extreme 16 loss of geneXc informaXon -> inferXlity; early miscarriage Rearrangement genetic disorders Freq (Aus) 1:2,500 1:10,000 (♀) 1:2,500 1:20,000 1:50,000 1:4,000 1:5,000 (♂) p and q refer to the arm of the chromosome, subsequent numbers indicate regions on the arms 17 Translocations Exchange of geneXc material between non-homologous chromosomes Three types of translocaXon events Balanced reciprocal – equal exchange, no loss of geneXc material Unbalanced reciprocal – unequal exchange, loss of geneXc material Robertsonian – unequal exchange on acrocentric chrs near centromere, loss of geneXc material Normal nonhomologous chromosomes (metacentric or submetacentric) This material oKen lost in cell divisions Normal nonhomologous chromosomes (acrocentric) Reciprocal – all chrs Robertsonian – chrs 13, 14, 15, 21, 22 18 Individual gene mutations 19 Structure of a gene Upstream regulatory elements Core promoter Start of transcription RNA produced Exon 1 Exon 3 Exon 2 DNA Intron 1 5’ UTR Start codon ATG Poly A site Intron 2 Translated region 3’ UTR Stop codon Promoter and upstream regulatory elements Exons and introns – instructions for pre-mRNA UTRs – untranslated regions for assisting translation and regulating expression 20 What is a mutation? A mutaNon is a change in the DNA sequence Produces a new allele (version) of a gene A wild-type allele is the most common version in a populaNon MutaNons increase geneNc variaNon and are the mechanism of evoluNon 21 Mutation locations A mutation event can occur anywhere along a DNA sequence 22 Mutation types 23 Missense mutations = Change one amino acid Nonsense mutations = Stop codon introduced 25 Inframe mutations = Add/delete a codon 26 Frameshift mutations = Add/delete part of a codon 27 Splice site mutations Specific sequence within intron guides splice location 28 Pedigrees 29 What is a pedigree A diagrammaNc representaNon of the geneNc history of a family Can be used to infer the inheritance paRern of geneNc disorders and map family disease/condiNon links Basic inheritance paRerns – autosomal or sex-linked; dominant or recessive Used when an individual has been diagnosed with a geneNc disorder/disease to find: - other at-risk family members - potenNal risks for offspring 30 Pedigree layout = female = male = affected individual = presenXng individual = carrier = miscarriage = unknown sex = deceased 31 Pedigree example Anne and David have three children – two girls and one boy. Anne has a genetic cardiac condition that several members of her family also have. Her brother died of sudden cardiac death at age 35 and her mother and sister are also affected by the same condition. Anne’s doctor has recommended that her children are screened for the condition and this shows her son to also be affected Draw the pedigree for this family reflecting the disease status and family relationships of all individuals 32 Pedigree example Anne and David have three children – two girls and one boy. Anne has a geneXc cardiac condiXon that several members of her family also have. Her brother died of sudden cardiac death at age 35 and her mother and sister are also affected by the same condiXon. Anne’s doctor has recommended that her children are screened for the condiXon and this shows her son to also be affected I II III 33 Summary Chromosomal rearrangements result in changes to chromosome set copy number, individual chromosome copy number or changes within an individual chromosome Polyploidy is not seen in humans but aneuploidy is Rearrangements within chromosomes includes deletion, duplication, inversion, translocation - translocations can be reciprocal or Robertsonian Rearrangements result in necessary changes to homologous chromosome alignment during subsequent meiosis These changes can have effects on the viability of gametes and therefore fertility Individual gene mutations are include insertions, deletions and substitutions These mutations are classed as nonsense or missense and inframe or frame shift depending on the effects to translation Pedigrees allow mapping of genetic disease/disorder throughout a family tree Can be used to infer genetic inheritance patterns 34 Thank you! 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