Overview of Human Genetics
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1 Overview of Human Genetics 1 Structure and function of nucleic acids. 2 Structure and composition of the human genome. 3 Mendelian genetics. Lander et al. (Nature, 2001) MAT 394 (ASU) Human Genetics Spring / 29
2 Nucleic Acid Structure DNA and RNA are polymers of nucleotides Nucleotides have three components: a 5-carbon sugar: deoxyribose (DNA) or ribose (RNA) 1-3 phosphate groups linked to the 5 carbon of the sugar a nitrogenous base linked to the 1 carbon of the sugar MAT 394 (ASU) Human Genetics Spring / 29
3 Nucleic Acid Structure Nucleic Acid Sugars Deoxyribose contains one less hydroxyl (-OH) group than ribose. The carbons are numbered clockwise 1-5. MAT 394 (ASU) Human Genetics Spring / 29
4 Nucleic Acid Structure Five Nitrogenous Bases A, T, C, G in DNA A, U, C, G in RNA MAT 394 (ASU) Human Genetics Spring / 29
5 Nucleic Acid Structure Nucleotides polymerize by forming phosphodiester bonds Polymerization proceeds 5 to 3 : RNA and DNA molecules grow by adding new nucleotides at the 3 end. Nucleic acids are oriented and by convention sequences are always written 5 to 3. Thus, ATTGCA ACGTTA. The addition of new nucleotides is catalyzed by a polymerase. Nucleotides can be removed by nucleases. MAT 394 (ASU) Human Genetics Spring / 29
6 Nucleic Acid Structure Pyrimidine-purine base pairs form by hydrogen bonding A-T and G-C base pairs have similar dimensions ( 2 nm). G-C base pairs have three H-bonds and are more stable than A-T base pairs. A-U base pairs can form in RNA. MAT 394 (ASU) Human Genetics Spring / 29
7 Nucleic Acid Structure Base pairing allows complementary strands to hybridize Hybridization occurs spontaneously between complementary ssdna under physiological conditions. Strands are anti-parallel, e.g., ATTGCA is complementary to TGCAAT. Hybridized strands melt (disassociate) at high temperatures. Key to replication and transcription of DNA and to many technologies: PCR, microarrays. MAT 394 (ASU) Human Genetics Spring / 29
8 Nucleic Acid Structure Complementary DNA strands form a double helix MAT 394 (ASU) Human Genetics Spring / 29
9 Nucleic Acid Structure dsdna wraps around histone octamers to form nucleosomes The core nucleosome consists of: histone octamer: two copies of H2A, H2B, H3, H4 147 bp DNA wrapped in 1.67 turns bp of linker DNA between nucleosomes Histones are highly conserved, positively-charged, and have tail domains that can be acetylated and methylated, affecting gene expression. MAT 394 (ASU) Human Genetics Spring / 29
10 Nucleic Acid Structure DNA is highly compacted with several levels of organization. Length of human genome is 2m (outstretched) Diameter of nucleus is 6µm MAT 394 (ASU) Human Genetics Spring / 29
11 Nucleic Acid Structure Topography of a chromosome Chromosomes have two arms, separated by a region known as the centromere. The p-arm is the smaller of the two arms; the q-arm is the larger. Chromosome ends are called telomeres. Certain dyes can be used to reveal a characteristic banding structure for each chromosome which depends on how condensed the chromatin is. These bands provide landmarks relative to which the locations of other features (genes, polymorphic markers) can be specified. human chromosome 10 MAT 394 (ASU) Human Genetics Spring / 29
12 Nucleic Acid Structure RNA is usually single stranded with intra-strand helices MAT 394 (ASU) Human Genetics Spring / 29
13 Nucleic Acid Functions Replication DNA replication is semiconservative Each copy contains one of the original strands and one new strand. MAT 394 (ASU) Human Genetics Spring / 29
14 Nucleic Acid Functions Protein synthesis The Central Dogma of Molecular Biology MAT 394 (ASU) Human Genetics Spring / 29
15 Nucleic Acid Functions Protein synthesis Proteins are polymers formed from 20 standard amino acids MAT 394 (ASU) Human Genetics Spring / 29
16 Nucleic Acid Functions Protein synthesis The amino acid sequence determines both the structure and function of a protein HIV-1 RT human hemoglobin MAT 394 (ASU) Human Genetics Spring / 29
17 Nucleic Acid Functions Protein synthesis The Genetic Code is Degenerate 20 amino acids 4 nucleotides 4 3 = 64 codons 1 start codon (AUG) 3 stop codons third position is often degenerate MAT 394 (ASU) Human Genetics Spring / 29
18 Nucleic Acid Functions Protein synthesis Eukaryotic genes contain coding and non-coding segments Introns are removed from the precursor mrna. MAT 394 (ASU) Human Genetics Spring / 29
19 Structure of the Human Genome The Human Karyotype Most human cells are diploid with 23 pairs of chromosomes. 22 pairs of autosomes X, Y sex chromosomes Exceptions: gametes are haploid and have 23 chromosomes; red blood cells lack nuclei altogether. MAT 394 (ASU) Human Genetics Spring / 29
20 Structure of the Human Genome Sex Chromosomes Sex determination in humans is chromosomal: XX individuals are female and XY individuals are male (usually). Humans are female by default: the presence of a particular Y-linked gene (SRY) is necessary and sufficient for development as a male. XXY and XYY individuals are male; XO and XXX individuals are female. There are rare instances of XY females due to inactivating mutations in the SRY gene. The X-chromosome is 155 mb long and contains around 2000 genes. The Y-chromosome is 59 mb long and contains around 200 genes. MAT 394 (ASU) Human Genetics Spring / 29
21 Structure of the Human Genome Contents of the Human Genome 3 billion base pairs per haploid complement 23, 000 protein-coding genes: exons (2%), introns (24%) transposable elements (51%) can move around the genome and many can replicate satellite DNA (6%) consists of non-coding tandem repeats Rollins et al. (Genome Research, 2006) MAT 394 (ASU) Human Genetics Spring / 29
22 Structure of the Human Genome Mitochondria also have genomes Human mt genome: circular bp 13 protein-coding genes 12S and 16S rrna genes 22 trna genes maternally-inherited Mitochondria are sub-cellular organelles where ATP is produced. Human cells contain 10 s to 1000 s mitochondria per cell. MAT 394 (ASU) Human Genetics Spring / 29
23 Mendelian Genetics Mitosis, Meiosis and Mendelian Genetics Eukaryotic cells can divide by two processes. Mitosis is the process by which diploid somatic cells divide in two. Apart from mutation, the daughter cells are genetically identical to the parent. Meiosis is the process by which diploid germ cells produce haploid gametes. This involves one round of DNA duplication, two rounds of cell division, and results in the production of four gametes. Mendelian genetics (Mendel, 1866) explains how offspring inherit genomes and traits from their parents. MAT 394 (ASU) Human Genetics Spring / 29
24 Mendelian Genetics Mendel s Law of Segregation An individual carries two copies of each locus called alleles. Homozygotes have two identical alleles (RR); heterozygotes have two different alleles (Rw). Each parent transmits just one of these two alleles to its offspring. Both copies are equally likely to be transmitted (usually). Usually, the sex of the parent contributing an allele doesn t matter, so that Rw and wr heterozygotes are indistinguishable. Genomic imprinting is an exception, affecting expression of human genes. MAT 394 (ASU) Human Genetics Spring / 29
25 Mendelian Genetics Mendel s Law of Independent Assortment Different chromosomes segregate independently. Loci on the same chromosome are usually inherited together, but can be reshuffled by recombination. Gametic phase cannot be directly inferred from single locus genotypes: an AaBb double heterozygote could be AB/ab or Ab/aB. MAT 394 (ASU) Human Genetics Spring / 29
26 Mendelian Genetics Crossing over during meiosis I produces recombinant gametes. MAT 394 (ASU) Human Genetics Spring / 29
27 Mendelian Genetics Recombination Rates Recombination (usually) occurs only between homologous chromosomes. Each pair of homologs undergoes at least one crossover during meiosis, but multiple crossovers can also occur. The probability that two loci recombine is an increasing function of the physical distance (number of basepairs) between them. MAT 394 (ASU) Human Genetics Spring / 29
28 Mendelian Genetics Non-recombining Markers The mitochondrion is maternally inherited and so its genome does not recombine. Most of the Y chromosome is non-recombining, except for two short terminal regions that recombine with the X (pseudo-autosomal regions). Recombination occurs along the entire length of the X chromosome in females. Non-recombining loci share the same genealogy, e.g., the entire mtdna genome has a single genealogical history. MAT 394 (ASU) Human Genetics Spring / 29
29 Mendelian Genetics References Alberts, B. et al. (2007) Molecular Biology of the Cell. 5 th edition. Garland Science. Krebs, J. E., Goldstein, E. S. and Kilpatrick, S. T. (2011) Lewin s Genes X. Jones and Bartlett. Sturtevant, A. H. and Lewis, E. B. (2001) A History of Genetics. Cold Spring Harbor Laboratory. MAT 394 (ASU) Human Genetics Spring / 29
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