Transcript Nutrition and Gene Expression Jan 29, 2015

Nutrition and Gene Expression
Jan 29, 2015
-The role of the X-chromosome in heredity
-Probability that recessive gene affects
offspring
-Mutations: how they occur, and when they
have effects on health
Female X-chromosome inactivation
At the 2000-cell stage (approximately), a change occurs in cells of embryos of
female mammals. It affects one of the X-chromosomes in each cell of the embryo.
ONE of the two X-chromosome becomes permanently inactive. All the cells that
descend from that cell show that pattern (except for cells that produce new ova).
Why is this important? It prevents the “double dose” effect: the level of protein
produced from either one of the active female X chromosomes is the same as the
level of protein made from the single male X chromosome.
The X chromosome that has been inactivated (called the Barr body) can be
seen along the edge of the nuclear membrane: it is very compact, similar to
chromosomes during mitosis, and its genes are mostly dormant.
Barr body (condensed
X-chromosome) in
female epithelial cell
(cell is NOT mitotic!)
Male epithelial cell:
no Barr body
If a sample of tissue from a female is examined, it is observed
that EITHER the maternal X or the paternal X chromosome is
active (in almost all cells). The active chromosome can differ between
adjacent tissues, as seen in a calico cat (which is always female). In the
black fur, there is activity of a different X chromosome than the tan fur.
What about human females? Does this pattern (called a mosaic) ever occur?
RARELY, if a woman has the gene for Duchenne’s muscular dystrophy on one X
chromosome, there will be SOME weakness in certain of her muscles where
that version of the X chromosome is not active. But it’s only a mild disorder, and
usually not a major problem. In a boy, with only that one copy of the gene, it’s a
VERY serious disorder.
Of some interest: about 1/3 of the time, an affected boy results from a NEW
mutation in the gene for the protein dystrophin. The other 2/3 of the time, the
mother is carrying the mutated gene on one of her two X-chromosomes.
Another disorder carried on the X-chromosome leads to defective sweat gland
production: heterozygous females may not be able to produce sweat from a
PORTION of their epidermis. Affected boys need to be VERY careful to avoid
being overheated, since they produce very little sweat at all.
There are LOTS of genes on the X-chromosomes, and we are slowly identifying
new genes where a mutation can be a serious problem for the male.
THE RIDDLE OF HOW X-LINKED MUTATIONS ARE NOT ELIMINATED BY
NATURAL SELECTION
The daughters are protected by the normal X, and can be healthy as carriers.
The recessive X-linked genes can be transferred through generations of girl
progeny to their offspring.
The X-chromosome, and any disorders linked to it, are also transmitted
by the mother to the male children, since a boy always gets X from the
mother and Y from the father.
Statistics of inherited autosomal traits (very simplified):
Suppose that 1% of the population carries a recessive trait
(green hair) on chromosome 14?
The odds of a marriage: 0.01 x 0.01 = .0001 = One in ten-thousand
This assumes equal odds for marriage, regardless of the recessive trait.
The odds of a child with green hair: from those marriages, only 1 offspring
in 4 will be affected = One in forty thousand.
The actual condition is FAR LESS prevalent than the recessive trait.
The formula to be used:
Rate of births with two recessive genes =
(Rate of carriers in the population)2 x 0.25.
Suppose the rate is only 0.001? Then:
(.001 x 0.001) x ¼ = .00000025 = one in four million (very rare disorder).
WE WILL WORK OUT EXAMPLES ON THE BOARD IN CLASS.
GRAPH: Percent of children with two recessive genes (y axis), as
a function of the the percent of people with one copy of the gene (x-axis).
This assumes that marriage frequency is INDEPENDENT of the
presence of the recessive gene.
Percent children with 2 copies
of the recessive trait
2.0
1.5
1.0
0.5
0.0
0
5
10
15
20
25
Percent in population with 1 copy
of the recessive trait
30
For example: 1 in 25 (4%) of the US population carries one allele of the cystic fibrosis
mutation (the recessive trait is protective against cholera and typhoid, so it persists)
About 1 birth in 2500 has actual cystic fibrosis (0.04 x 0.04 x 0.25).
The gene is for a protein that regulates a chloride channel. If you have
one good copy of the gene, you have no problems of any kind.
If you have two defective copies: The disease is very very bad.
Question for consideration: should screening for the CF gene be made
generally available, so people can make reproductive decisions?
The gene for the
chloride channel
regulator (CFTR)
is found on
Chromosome 7.
In 75% of cases, the protein for the
chloride channel regulator is missing the
codon for an entire amino acid (Phe).
As a result of the mutation, chloride and
sodium transport are not normal.
1
2
3
6
7
8
13
14
15
16
17
18
20
21
22
XY
19
4
9
10
5
11
12
Complete human chromosomes (Male), as seen during
MITOSIS. The banding patterns are very distinctive, and
allow each chromosome to be identified.
DNA AND GENETIC DISORDERS
THE MAJORITY OF GENETIC DISORDERS ARE
THE RESULT OF PROBLEMS THAT OCCUR
IN MEIOSIS, OR FROM INHERITING TWO
COPIES OF A RECESSIVE GENE.
Problems in newborns from simple mutations
are less common. The mutation rate is very low:
the genes that a child inherits usually only differ
at about 100 base pairs, from the genes in the
parental DNA. Most of those sequence changes
are harmless.
WHAT CAN HAPPEN DURING MEIOSIS?
For example. sometimes a chromosome (such
as Chromosome 21) is copied twice during the
formation of gametes (usually an ovum).
TRISOMY 21: visualized from
metaphase chromosomes
The baby gets THREE copies: two maternal, and
one paternal.
It’s called Trisomy 21. There are many other
trisomies, but most of them are embryonic
lethal. We know about Trisomy 21, because
children with that disorder often grow to
reach adulthood.
Prenatal diagnosis is
now fairly simple. and is
now a common procedure.
DNA REPLICATION: If every gene was
copied perfectly, the genes in the gametes
would be identical to the parental genes.
This is what is supposed to happen
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
TWO EXACT COPIES
OF ORIGINAL DNA
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
BUT ONE COPY CAN HAVE THE
WRONG DNA BASE!
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
TACGATTACACAGATATATGC
DEFECTIVE COPY
ATGCTAATGTGTCTAT ATACG
A WHOLE REGION CAN BE DELETED
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
TACGATTACACGGATATATGC
ATGCTAATGTGCCTAT ATACG
This copy has lost
3 bases from each strand
TACGATTACACGATATGC
ATGCTAATGTGCTATACG
You will be given a homework
assignment to help you consider
the EFFECTS that might occur
with different mutations.
How do we sequence genes? Using the most common technology, we prepare
a large number of copies of a short DNA region (500-800 base pairs). We then
sequence the region that with a method called DIDEOXY SEQUENCING.
This provides the sequence for that DNA region.
The company “23 AND ME” will give you a report on some of the important
sequence variants, which we will discuss in class next week.
Technology is moving very fast: we are in the DEEP-SEQUENCING ERA.
There are companies that will now sequence your entire genome for $5,000.
The goal is to provide that for less than $1,000 (certain to be achieved soon).
Of course, if your doctor has your COMPLETE DNA sequence, what
use can be made of that? VERY CONTROVERSIAL.
For example: we have lists of thousands of recessive and dominant mutations
that cause health disorders. This technology will tell you which of
these recessive genes (there are probably several) are in your genome.