Download Lecture 4 Linkage and Recombination

Lecture 4 Linkage and Recombination
CAMPBELL BIOLOGY
Chapter 9
Notes at: tcd.ie/Biology_Teaching_Centre/local/
junior-freshman/ ≠≠ by1101local
This is an Irish family with an autosomal dominant disease
mutation which causes blindness (the disease is called RP).
A large family like this is powerful (statistically) & can be
used to find out which human chromosome the disease
gene is on. This lecture is about the basis of genetic linkage
mapping which allows us to localise disease genes. Central
to this is the concept of crossing/ over recombination
during Prophase I of meiosis which we discussed in the last
lecture (lecture 3). Let’s go thru’ some background first......
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Genes are located on Chromosomes
•  During the 19th century, cytologists identified chromosomes
and described their behaviour during mitosis and meiosis
•  They did not realise that chromosomes were involved in the
mechanism of inheritance
•  In the early 20th century, geneticists realised that chromosomes
behaved just like the hypothetical unit factors proposed by
Mendel to explain inheritance
- they occur in pairs in diploid cells
- their number is halved during gamete formation
- fertilisation restores the diploid number
•  They eventually proved that genetic information (genes) is
located on the chromosomes
Mendel s studies
•  Mendel investigated the inheritance of 7 traits
•  Each trait showed independent assortment
i.e. the inheritance of one trait did not influence
the inheritance of the second trait
•  Because of this, he observed the following ratios in the offspring
1. Monohybrid cross (inheritance of a single trait)
3 : 1 (dominant : recessive)
2. Dihybrid cross (inheritance of two traits)
9:3:3:1
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Is independent assortment always the case? No
it depends on whether the genes are linked or not
(a) Genes located on different chromosomes are not linked
This allows independent assortment – in a di-hybrid cross
the traits show the classic 9:3:3:1 inheritance pattern
(b) Genes that are located very close together on the same
chromosome may show complete linkage
They may be so close to each other that they cannot be
separated by recombination during meiosis
(c) Genes located far apart on the same chromosome
typically show incomplete (partial) linkage
because they are easily separated by recombination
Linkage
Humans contain approximately 25,000 genes (haploid number)
But there are only 23 chromosomes (diploid number 2n = 46)
Clearly, there are hundreds / thousands of genes on a given
chromosome
All of the genes on a given chromosome are said to be linked
or to belong to the same linkage group
IMPLICATIONS OF LINKAGE
Since chromosomes are the units that are distributed into gametes
during meiosis, if 2 genes are located on the same chromosome
they will tend to be inherited together whereas genes located on
different chromosomes will show independent inheritance.
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A di-hybrid cross between 2 fruit flies (Drosophila)
We re using the fruit fly, Drosophila, as an example – the same
rules apply to inheritance of two human traits.
grey (wild-type)
b+
DOMINANT
black (mutant)
b
recessive
large (wild-type)
vg+
Trait 1 = body colour
DOMINANT
Trait 2 = wing size
vestigial (mutant) vg
recessive
Genetic Map of Chromosome 2 of Drosophila
b+
vg+
b
vg
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b+
vg+
b
vg
Sometimes a
crossing over
event during
meiosis will
occur giving
new non-parental
genotypes:
b+ vg
and
b vg+
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Why so many parental types in the offspring?
The 2 genes are not showing independent assortment
because they are linked i.e. are on the same chromosome
Mother
Father
Why are there any non-parental types (i.e. recombinants)?
Answer: In this case because of recombination/crossing over in the female fly
Cross overs between
non-sister chromatids
Meiosis II
Types of gametes
produced
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http://www.uic.edu/classes/bms/bms655/lesson12.html
Haemophilia A (Factor VIII) – bleeding disorder
G6PD deficiency – hemolytic anemia
Recap from Lecture 3
Meiosis Prophase I (Crossing-over /
recombination)
•  Homologous chromosomes (each consisting
of two sister chromatids) come together as
pairs
•  The structure formed is called a tetrad
•  Chromosome segments are swapped between
non-sister chromatids at cross-over points
called chiasmata (= crossing-over)
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Genetic maps or linkage maps
Sturtevant proposed that recombination frequencies
reflect the distances between genes on a chromosome
It is assumed that the chances of crossing over is equal at
all points on a chromosome
If so, then the farther apart two genes are:
(a) the higher the probability that a cross-over will occur
between them and therefore
(b) the higher the recombination frequency
Why? Because the greater the distance between two genes
the more points there are between them where
crossing over can occur
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Recombination frequencies can be used to construct
a genetic map
• 
Recombination frequencies are approximately additive
• 
Recombination frequency between the body colour gene black
(b) and the eye colour gene cinnabar (cn) = 9%
• 
Recombination frequency between cinnabar and
vestigial wing (vg) = 9.5%
• 
Recombination frequency between b and vg = 17%
1% recombination
equates to approx.
1 million base pairs of
DNA (also termed
1 centiMorgan (cM) after
the scientist Morgan)
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Co-inheritance
of a marker &
disease gene
helps localise
the disease gene
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A1618
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www.csc.fi/english/csc/publications/cscnews/2009/2/twins_genetics_research
‘A genetic map of the genes affecting adult height. Genetic linkage analysis was used for locating genes affecting stature. This method utilizes
genetic markers known to show variation between individuals. The markers are evenly distributed across the entire genome and they are
determined from DNA samples. By using these markers it is possible to determine, by means of the linkage analysis, the chromosomal regions
that are similar in family members showing a strong correlation in height. As a result, scientists can estimate the statistical probability of the
region containing genes associated with adult stature. Statistical significance for the detected linkages must then be determined through computer
simulation.’
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