Overview of Human Genetics - Arizona State Universityjtaylor/teaching/Spring2014/MAT...Overview of...
Transcript of Overview of Human Genetics - Arizona State Universityjtaylor/teaching/Spring2014/MAT...Overview of...
Overview of Human Genetics
1 Structure and function of nucleicacids.
2 Structure and composition of thehuman genome.
3 Mendelian genetics.
Lander et al. (Nature, 2001)
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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 tothe 5’ carbon of the sugar
a nitrogenous base linked tothe 1’ carbon of the sugar
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Nucleic Acid Structure
Nucleic Acid Sugars
Deoxyribose contains one less hydroxyl (-OH) group than ribose.
The carbons are numbered clockwise 1’-5’.
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Nucleic Acid Structure
Five Nitrogenous Bases
A, T, C, G in DNA
A, U, C, G in RNA
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Nucleic Acid Structure
Nucleotides polymerize by forming phosphodiester bonds
Polymerization proceeds 5’ to 3’: RNAand DNA molecules grow by adding newnucleotides at the 3’ end.
Nucleic acids are oriented and byconvention sequences are always written5’ to 3’. Thus, ATTGCA 6= ACGTTA.
The addition of new nucleotides iscatalyzed by a polymerase.
Nucleotides can be removed by nucleases.
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Nucleic Acid Structure
Pyrimidine-purine base pairs form by hydrogen bonding
A-T and G-C base pairs have similardimensions (∼ 2 nm).
G-C base pairs have three H-bondsand are more stable than A-T basepairs.
A-U base pairs can form in RNA.
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Nucleic Acid Structure
Base pairing allows complementary strands to hybridize
Hybridization occurs spontaneouslybetween complementary ssDNAunder physiological conditions.
Strands are anti-parallel, e.g.,ATTGCA is complementary toTGCAAT.
Hybridized strands ‘melt’(disassociate) at high temperatures.
Key to replication and transcriptionof DNA and to many technologies:PCR, microarrays.
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Nucleic Acid Structure
Complementary DNA strands form a double helix
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Nucleic Acid Structure
dsDNA wraps around histone octamers to form nucleosomes
The core nucleosome consists of:
histone octamer: two copiesof H2A, H2B, H3, H4
147 bp DNA wrapped in1.67 turns
50-70 bp of linker DNAbetween nucleosomes
Histones are highly conserved, positively-charged, and have tail domainsthat can be acetylated and methylated, affecting gene expression.
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Nucleic Acid Structure
DNA is highly compactedwith several levels oforganization.
Length of humangenome is ∼ 2m(outstretched)
Diameter of nucleus is∼ 6µm
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Nucleic Acid Structure
Topography of a chromosome
Chromosomes have two arms, separatedby a region known as the centromere.
The p-arm is the smaller of the twoarms; the q-arm is the larger.
Chromosome ends are called telomeres.
Certain dyes can be used to reveala characteristic banding structure for eachchromosome which depends on howcondensed the chromatin is.
These bands provide landmarks relativeto which the locations of other features(genes, polymorphic markers) can be specified.
human chromosome 10
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Nucleic Acid Structure
RNA is usually single stranded with intra-strand helices
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Nucleic Acid Functions Replication
DNA replication is semiconservative
Each copy contains one of the original strands and one new strand.
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Nucleic Acid Functions Protein synthesis
The Central Dogma of Molecular Biology
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Nucleic Acid Functions Protein synthesis
The Genetic Code is Degenerate
20 amino acids
4 nucleotides
43 = 64 codons
1 start codon (AUG)
3 stop codons
third position isoften degenerate
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Nucleic Acid Functions Protein synthesis
Eukaryotic genes contain coding and non-coding segments
Introns are removed from the precursor mRNA.
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Structure of the Human Genome
The Human Karyotype
Most human cells are diploidwith 23 pairs of chromosomes.
22 pairs of autosomes
X, Y sex chromosomes
Exceptions: gametes arehaploid and have 23chromosomes; red bloodcells lack nuclei altogether.
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Structure of the Human Genome
Sex Chromosomes
Sex determination in humans is chromosomal: XX individuals arefemale and XY individuals are male (usually).
Humans are female by default: the presence of a particular Y-linkedgene (SRY) is necessary and sufficient for development as a male.
XXY and XYY individuals are male; XO and XXX individuals arefemale.
There are rare instances of XY females due to inactivating mutationsin the SRY gene.
The X-chromosome is 155 mb long and contains about 1, 846 genes.
The Y-chromosome is 58 mb long and contains about 80 genes.
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Structure of the Human Genome
Contents of the Human Genome
3 billion base pairs per haploidcomplement
23, 000 protein-coding genes:exons (2%), introns (24%)
transposable elements (51%)can move around the genomeand many can replicate
satellite DNA (6%) consists ofnon-coding tandem repeats
Rollins et al. (Genome Research, 2006)
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Structure of the Human Genome
Mitochondria also have genomes
Human mt genome:
circular
16569 bp
13 protein-coding genes
12S and 16S rRNA genes
22 tRNA genes
maternally-inherited
Mitochondria are sub-cellular organelles where ATP is produced. Humancells contain 10’s to 1000’s mitochondria per cell.
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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 tothe parent.
Meiosis is the process by which diploid germ cells produce haploidgametes. This involves one round of DNA duplication, two roundsof cell division, and results in the production of four gametes.
Mendelian genetics (Mendel, 1866) explains how offspring inheritgenomes and traits from their parents.
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Mendelian Genetics
Mendel’s Law of Segregation
An individual carries two copies ofeach locus called alleles.
Homozygotes have two identicalalleles (RR); heterozygotes havetwo different alleles (Rw).
Each parent transmits just one ofthese two alleles to its offspring.
Both copies are equally likely to betransmitted (usually).
Usually, the sex of the parent contributing an allele doesn’t matter, so thatRw and wR heterozygotes are indistinguishable. Genomic imprinting isan exception, affecting expression of about 80 human genes.
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Mendelian Genetics
Mendel’s Law of Independent Assortment
Different chromosomes segregateindependently.
Loci on the same chromosomeare usually inherited together,but can be reshuffled byrecombination.
Gametic phase cannot bedirectly inferred from singlelocus genotypes: an AaBbdouble heterozygote couldbe AB/ab or Ab/aB.
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Mendelian Genetics
Crossing over during meiosis I produces recombinant gametes.
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Mendelian Genetics
Recombination Rates
Recombination (usually) occurs only between homologouschromosomes.
Each pair of homologs undergoes at least one crossover duringmeiosis, but multiple crossovers can also occur.
The probability that two loci recombine is an increasing function ofthe physical distance (number of basepairs) between them.
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Mendelian Genetics
Non-recombining Markers
The mitochondrion is maternally inherited andso its genome does not recombine.
Most of the Y chromosome is non-recombining,except for two short terminal regions thatrecombine with the X (pseudo-autosomalregions).
Recombination occurs along the entire lengthof the X chromosome in females.
Non-recombining loci share the same genealogy,e.g., the entire mtDNA genome has a singlegenealogical history.
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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’sGenes X. Jones and Bartlett.
Sturtevant, A. H. and Lewis, E. B. (2001) A History of Genetics. ColdSpring Harbor Laboratory.
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