Download Human Genetics

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 2012
1 / 27
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 2012
2 / 27
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 2012
3 / 27
Nucleic Acid Structure
Five Nitrogenous Bases
A, T, C, G in DNA
A, U, C, G in RNA
MAT 394 (ASU)
Human Genetics
Spring 2012
4 / 27
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 6= ACGTTA.
The addition of new nucleotides is
catalyzed by a polymerase.
Nucleotides can be removed by nucleases.
MAT 394 (ASU)
Human Genetics
Spring 2012
5 / 27
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 2012
6 / 27
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 2012
7 / 27
Nucleic Acid Structure
Complementary DNA strands form a double helix
MAT 394 (ASU)
Human Genetics
Spring 2012
8 / 27
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
50-70 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 2012
9 / 27
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 2012
10 / 27
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.
MAT 394 (ASU)
Human Genetics
human chromosome 10
Spring 2012
11 / 27
Nucleic Acid Structure
RNA is usually single stranded with intra-strand helices
MAT 394 (ASU)
Human Genetics
Spring 2012
12 / 27
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 2012
13 / 27
Nucleic Acid Functions
Protein synthesis
The Central Dogma of Molecular Biology
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Human Genetics
Spring 2012
14 / 27
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 is
often degenerate
MAT 394 (ASU)
Human Genetics
Spring 2012
15 / 27
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 2012
16 / 27
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 2012
17 / 27
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 about 1, 846 genes.
The Y-chromosome is 58 mb long and contains about 80 genes.
MAT 394 (ASU)
Human Genetics
Spring 2012
18 / 27
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 2012
19 / 27
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. Human
cells contain 10’s to 1000’s mitochondria per cell.
MAT 394 (ASU)
Human Genetics
Spring 2012
20 / 27
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 2012
21 / 27
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 about 80 human genes.
MAT 394 (ASU)
Human Genetics
Spring 2012
22 / 27
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 2012
23 / 27
Mendelian Genetics
Crossing over during meiosis I produces recombinant gametes.
MAT 394 (ASU)
Human Genetics
Spring 2012
24 / 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 2012
25 / 27
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 2012
26 / 27
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 2012
27 / 27