Linking chromosomes to genetics

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Welcome back to IB 150...
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Five general categories of genetic disorders exist

• Single gene (Mendelian) disorders
• Polygenic (multifactorial) traits
• Mitochondrial diseases
• Chromosomal abnormalities (Lecture 10)
• Diseases of unknown etiology (causes) that run
  in families

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Mitochondrial DNA

• Humans 16,000 bases
• Not a linear chromosome
• Similar to bacterial DNA
• Genes for rRNA (2), tRNA (22), 13 proteins in the
  electron transport chain that produces ATP

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(No Transcript)
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Mitochondrial inheritance
Maternal inheritance
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Mitochondrial Patterns of Inheritance
Most mitochondrial genes are associated
with Metabolism - energy production - so
mitochondrial disorders often involve metabolism
(Lebers hereditary optic neuropathy - causes
loss of central vision - not enough cellular
energy provided to the cells in the retina)
In this case pedigree analysis is simple
All children of affected males WILL NOT inherit
the disease.  All children of affected females
WILL inherit it. There are NO carriers.
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Genetic diseases to know for IB150

• Tay-Sachs disease single gene, autosomal
  recessive, early lethal, no homozygotes
  reproduce, carriers have normal phenotype
• Sickle cell anemia single gene, autosomal
  recessive, condition can be treated, carriers may
  have symptoms (sickle cell trait)
• Cystic fibrosis single gene, autosomal
  recessive, life can be prolonged, carriers have
  normal phenotype
• Phenylketonuria (PKU) single gene, autosomal
  recessive, can be diagnosed at birth, diet can
  treat, carriers have normal phenotype
• Huntingtons disease single gene, autosomal
  dominant, onset late in life (so patients likely
  to reproduce prior to diagnosis), no carriers
• Heart disease, high blood pressure multiple
  genes, no simple pattern of inheritance, genes
  increase susceptibility
• Lebers hereditary neuropathy mitochondrial,
  relatively late onset, inherited from mother only

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Genetic diseases to know for IB150

• Tay-Sachs disease single gene, autosomal
  recessive, early lethal, no homozygotes
  reproduce, carriers have normal phenotype (p.
  261)
• Sickle cell anemia single gene, autosomal
  recessive, condition can be treated, carriers may
  have symptoms (sickle cell trait) (p. 267)
• Cystic fibrosis single gene, autosomal
  recessive, life can be prolonged, carriers have
  normal phenotype (p. 266)
• Phenylketonuria (PKU) single gene, autosomal
  recessive, can be diagnosed at birth, diet can
  treat, carriers have normal phenotype (p.
  269-270)
• Huntingtons disease single gene, autosomal
  dominant, onset late in life (so patients likely
  to reproduce prior to diagnosis), no carriers (p.
  268)
• Heart disease, high blood pressure multiple
  genes, no simple pattern of inheritance, genes
  increase susceptibility (p. 268)
• Lebers hereditary neuropathy mitochondrial,
  relatively late onset, inherited from mother only
  (not in book see p. 289-290)

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Lecture 8 Mendelian Inheritance in Humans
Readings Ch. 14
Understand the use of pedigree analysis to
determine patterns of inheritance in humans.
inherited disorders genetic diseases.  Name the
5 categories of genetic diseases observed in
humans. single gene disorders multifactorial
(polygenic) traits chromosomal abnormalities
mitochondrial inheritance diseases of unknown
etiology Identify the conventional symbols used
to depict human family trees. pedigree Name the
5 categories of single gene (Mendelian)
disorders. autosomal recessive autosomal
dominant multifactorial, chromosomal, and
mitochondrial, unknown etiology
 Give examples of autosomal recessive traits and
be able to identify the pattern of inheritance.
cystic fibrosis Tay-Sachs sickle cell
disease Give examples of autosomal dominant
traits and be able to identify the pattern of
inheritance. Huntington Disease Give examples of
mitochondrial traits and be able to identify the
pattern of inheritance. Lebers hereditary
optic neuropathy
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Lecture 9 Linkage
Readings Ch. 15, up to 15.3
Understand that Mendels laws have a physical
basis. locus, linkage, linked,
syntenic Understand that there can be many genes
on a single chromosome. linkage  Associate
Thomas Hunt Morgan with the fruit fly, Drosophila
melanogaster. wild-type phenotype mutant
phenotype natural mutations induced mutations.
 Understand that unlinked genes are recombined by
independent assortment understand that linked
genes may be recombined during crossing-over. par
ental types recombinants. Use recombination data
to map the location of genes on chromosomes.
linkage map, map distance
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What is linkage?

• Locus position of a gene on a chromosome
• Genes on the same chromosome are said to be
  syntenic
• Genes physically close together on a single
  chromosome are more likely to stay together
  during crossing-over, and are linked - they are
  inherited together, or cosegregate
• Genes farther apart on a chromosome are more
  likely to be recombined during crossing-over - if
  far enough apart, they show independent
  assortment
• The phenomenon of recombination was first
  described by T.H. Morgan for fruit flies

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Mitotic metaphase chromosome, showing chromatin
fibers containing DNA. Each gene occurs on a
specific place (locus) on the chromosome on which
it is located. There is a molecular technique
that allows us to visually show where a gene is.
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Mitotic metaphase chromosome, showing chromatin
fibers containing DNA. Each gene occurs on a
specific place (locus) on the chromosome on which
it is located. There is a molecular technique
that allows us to visually show where a gene is.
the location of a particular gene
But in actuality, the label attaches to a strand
of DNA, and the color mark only looks like a blob.
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Fig. 15.1
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Normal double-stranded DNA, still in chromosome.
Denatured (heated) single-stranded DNA, still in
chromosome.
A probe of complementary single-stranded DNA a
fluorescing molecule
Hybridization of probe to DNA in chromosome.
FISH
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But to consider yourself to be a real
geneticist, you need to be able to understand how
genetic maps - graphs showing the location of
genes - were constructed for the first 80 years
of genetics - are are still constructed
today.We will now learn how to construct a
recombinational map, also called a genetic
map. This is different from a physical map based
on FISH and/or DNA squencing of entire genomes.
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Crosses can only be understood with respect to
meiosis.
Fig. 15.2
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T. H. Morgan first showed, using a recessive
white eye mutant of the common fruit fly
Drosophila melanogaster, that a gene had to be
located on a specific chromosome.
Fig. 15.3
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Yet another way of naming alleles Gene name an
italicized letter or letters, superscripted with
a for the wild type allele - the allele seen
commonly in nature. Thus, for the white eye gene
of Drosophila melanogaster, the two common
alleles are w - dominant, red eyes
(wild-type). w - recessive, mutant, white eyes.
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Why do white eyes occur only in males in the F2
generation?
Fig. 15.4
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Drosophila melanogaster Meigen
wild-type female
ebony body, vestigal winged male
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If these two fly genes were on different
chromosomes, then we would expect to see
independent assortment of the kind Mendel saw for
pea color and smoothness.
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But if the two genes were on the same chromosome,
we should see dependent assortment - ebony color
should stay with vestigal wings in all (or at
least most) progeny in the F2.
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What Morgan actually saw - lots of parental
chromosomes, but also some recombinant phenotypes.
Fig. 15.5
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An explanation for recombinant phenotypes in
terms of crossing-over between homologous
chromosomes.
Fig. 15.6
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What is the highest percent recombination that
can be measured in a dihybrid testcross?
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What is the highest percent recombination that
can be measured in a dihybrid testcross?
The highest percent recombination that can be
measured is 50. This is the same value as in
the case of independent assortment. If two genes
are very far apart, they will be inherited as if
they were on different chromosomes - even if they
are truly on the same chromosome. This is
because almost every meioisis will have a
crossover.
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But what about multiple crossovers?
centromere
Chiasmata (2 of them) in meiosis in a salamander.

Fig. 13.11 (similar)
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a
b
Even multiple crossovers produce 1/2 parental
gametes, and 1/2 recombinant gametes.
b
a
A
B
A
B
a
b
b
a
A
B
A
B
a
B
A
B
a
b
b
A
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What is the highest percent recombination that
can be measured in a dihybrid testcross?
The highest percent recombination that can be
measured is 50. This is the same value as in
the case of independent assortment. If two genes
are very far apart, they will be inherited as if
they were on different chromosomes - even if they
are truly on the same chromosome.
Genes that are on the same physical chromosome
are said to be syntenic (on the same thread),
even if they are so far apart that they show
independent assortment.
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The percent recombination value is used a a
recombinational map distance in genetics.
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The percent recombination value is used a
recombinational map distance in genetics.
But is is transformed so it is not written
exactly as a percentage. We use a unit called a
centiMorgan, or cM. One percent recombination is
1 cM.
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• Fig. 15.7. Sturtevant used the test cross design
  to map the relative position of three fruit fly
  genes, body color (b), wing size (vg), and eye
  color (cn). He found that by making all possible
  dihybrid crosses, he could deduce the gene order.
• The recombination frequency between cn and b is
  9.
• The recombination frequency between cn and vg is
  9.5.
• The recombination frequency between b and vg is
  17.
• The only possible arrangement of these three
  genes places the eye color gene between the
  other two.

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Fig. 15.7. But why is 17 a little less than 9
9.5 18.5? Sturtevant found the answer by
making trihybrid crosses and looking carefully at
all possible progeny.
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Why dont the numbers add up?

• The three recombination frequencies in our
  mapping example are not quite additive 9 (b-cn)
  9.5 (cn-vg) 17 (b-vg).
• This results from multiple crossing-over events.
• A second crossing-over cancels out the first
  and reduces the observed number of recombinant
  offspring.
• Genes farther apart (for example, b-vg) are more
  likely to experience multiple crossing-over
  events.

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vg
cn
b
vg
b
cn
vg
cn
b
b
cn
vg
If you consider only the b and vg genes, the
gametes produced are all either b vg or b vg,
even though there has been crossing-over between
them. So you need to do a trihybrid cross to be
able to determine the true map distance between
genes.
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A recombinational map for few genes of
Drosophila chromosome 2.
Fig. 15.8
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Today, recombinational or genetic maps are
combined with physical maps to produce a complete
understanding of the relative location of
genes. Physical maps can be of several kinds.
Two very important ones are Cytogenetic
(chromosomal) maps using technologies like
FISH. Genomic maps from sequencing projects
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A comparison of a recombination map (distances
not shown, only relative gene order) and a
physical map (FISH), for chromosome 11 in people.
Dr. Julie R. Korenberg Neurogenetics,
UCLA. http//www.csmc.edu/csri/korenberg/images/pa
pers/figure2.jpg
page www.csmc.edu/csri/korenberg/chroma11.html
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A comparison of genetic and physical maps in
rice. The gene names are in red at the right,
with their genetic position (cM from the end of
the chromosome) in black next to them. The red
line is the physical map in kb. The total genome
size is 430 mb (million base pairs), so each
chrmosome is about 383 kb long.
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Lecture 9 Linkage
Readings Ch. 15, up to 15.3
Understand that Mendels laws have a physical
basis. locus, linkage, linked,
syntenic Understand that there can be many genes
on a single chromosome. linkage  Associate
Thomas Hunt Morgan with the fruit fly, Drosophila
melanogaster. wild-type phenotype mutant
phenotype natural mutations induced mutations.
 Understand that unlinked genes are recombined by
independent assortment understand that linked
genes may be recombined during crossing-over. par
ental types recombinants. Use recombination data
to map the location of genes on chromosomes.
linkage map, map distance