20 October 2004
omit text question 5.16
answer question asked
again, answers to work book questions in the back of the workbook
importance of recitations this week
Chapter 21 mutations
First, some simple ideas relative to mutations ... not in text
gene and chromosomal mutations
forward and back mutations
somatic; germinal;
timing of mutations;
early or late in the development of an organism EarlyLateMuts.gif
types of mutations
then, Detection systems for a specific gene (Why are some mutations so
difficult to detect?):
Tradescantia KU-9
from blue to pink
a triploid; B = blue, b= pink; KU-9 is Bbb
KU-9 flowers .........ku9-1.GIF
KU-9 staminal hairs .......KU9-3.GIF
Ichikawa, S., et al. 1996 Yearly variation of spontaneous somatic
mutation frequency in the stamen hairs of Tradescantia
clone KU 9 grown outdoors, which showed a significant
increase after the Chernobyl accident. Mutat Res
349(2): 249-59.
and, Detection systems for genes on the x-chromosome:
By Herman Muller, student of T. H. Morgan
ClB technique ..... as a sequence... ClBsequence.html
Components of the ClB technique - must know purpose of each
C = crossover suppresser, dominant
"gene" preventing crossing over in the heterozygote
l = a built in recessive
lethal mutation, kills half of the males in the F2
B = dominant bar eye
mutation, allows detection of F-1 with C and l
m = an induced recessive
x-linked lethal mutation used for teaching purposes
ClB technique
hand out...............ClB01.GIF
the genes ..............ClB02.GIF
the genotypes ........ClB03.GIF
Punnett square .......clb04.GIF
Jenny and Paul ...............ClB05.GIF
Paul and his sperm ............... ClB06.gif
Jenny and her eggs ............... ClB07.GIF
Three of Jenny and Paul's Daughters
Nancy ............... ClB08.GIF
Leanne ............... ClB09.GIF
Danielle ............... ClB10.GIF
conclusion .............ClB11.GIF
Review of ClB via a problem
another problem .....clb12.gif
Muller's Graph ....
Muller Nobel Prize 1946....Photos.... MullerPhotos.GIF (not
web)
Muller and sperm banks:
"The widow of Nobel Prize-winning geneticist Hermann J. Muller
says she is upset a California businessman
named a sperm bank after her husband. Tea Muller
said yesterday in Bloomington Ind., she had denied
use of her husband's name for the project - the Hermann
J. Muller Repository for Germinal Choice - which matches
genes of Nobel Prize-winning scientists with bright women.
Robert K. Graham of Escondido, Calif., who established
the sperm bank, has......."
Boston Globe 4 March 1980
http://www.boston.com/globe/search/stories/Nobel/1980/1980ar.html
Muller became involved with communism and the Soviet Union; There is
an interesting story of genetics in the Soviet Union at that time: Read the
book by Medvedev if interested.
Medvedev, Ahores A. 1969 The rise and fall of T.D. Lysenko. Columbia
University Press
More recently: Effect of low level radiation
Greene, G. 1999. The woman who knew too much: Alice Stewart and
the secrets of radiation. The University of Michigan Press, Ann Arbor.
"In 1956, British physician Alice Stewart discovered that exposing
a fetus to a single diagnostic X-ray doubles
the risk of an early death from cancer."
And chemical mutagenesis: Charlotte Auerbach (1899-1994)
Genetics 1995 141: 1-5.
above: not in text
Summary: A new study from Oxford University in the UK has estimated
the risk of cancer on the basis of the annual number of diagnostic
X-rays done in the UK and 14 other countries, including Canada
and the US. Around 700 cases of cancer diagnosed annually in the
UK could be attributable to exposure to diagnostic X-rays. In the
US, it is estimated that nearly 5,700 cancer cases a year may be
due to diagnostic X-rays
Reference PSU library: http://vikat.pdx.edu/search/tlancet/tlancet/1,3,4,B/l856&FF=tlancet&1,,2,1,0
25 October 2004
An exciting morning!!
Use and Abuse of Science Wednesday, 6-7:30 PM SMC cafeteria,
27 October 2004 ...... ../UseAbuseScience.gif
Platypus, 2n=52, has 10 sex chromosomes 5 X-chromosomes, 5 Y-chromosomes,
sex determination a mixture of bird and mammal; paper in Nature.
Junk DNA, no effect on development in mice...... Nobrega, M. A., Y. Zhu,
et al. (2004). "Megabase deletions of gene deserts result in viable
mice." Nature 431(7011): 988-93.
Critical region for Down Syndrome ... Nelson, D. L. and R. A.
Gibbs (2004). "Genetics. The critical region in trisomy 21." Science 306(5696):
619-21.
The second midterm exam date is almost here. The final exam is
not that far away. We will miss two sets of recitation due to hollidays.
There will be no recitations during the weeks of 7 and 21 November.
It is important that you keep up to date with your studies. We
continue to move along quickly. You should have completed the chromosome
mutation table by the end of this week. I want you to do it; there
will be no key.
Last lecture we looked at the duplication and deletion and started on
the inversion
We talked a bit about the chromosome mutation chart. Examples of
the model were given.
Note some of the key ideas: the difference between the three chromosome
types; the heterozygote may indicate the nature of the mutation; the
heterozygote is best; the matching of numbers; the desire for close pairing
of homologues;
Chromosome structural mutations
We will look at some of the major chromosome mutations.
As a way of keeping tract and comparing them I ask you to fill in the
chromosome mutation
chart on page 37 of the workbook. The chart is compressed,
so you may wish to make a larger copy. In lecture
I will discuss the chart items. Hopefully, you will be
able to fill in the chart on your own after listening to the
lectures, observing the lecture materials and studying the
web materials.
The chart is easy if you know some basic ideas .... like ....Table help
Workbook page 35-36: We may manipulate ideograms of chromosomes to get
some idea about how real karyotypes will look.
Kinds of chromosomes
more polytene chromosomes... polytenes.gif
advantages and disadvantages of each type of chromosome?
The human geneticist is usually limited to an analysis of mitotic
chromosomes. Why?
Chromosome markers
euchromatin
and heterochromatin
simple statement:
during interphase euchromatin is diffuse
and lightly stained; during interphase heterochromatin
is tightly coiled and stains darkly.
mitotic banding...
Centromeric heterochromatin . C-banding.gif
to see this picture on your computer check out: Univ
Washington Pathology ...a beautiful
Web site on chromosome banding
Chromosome mutations
Overview
change may be within or between chromosomes
change within chromosomes may be homozygous or heterozygous
peculiar structures may be seen in heterozygotes for paired
chroms.
IMPORTANT: Paired chromosomes are best for detection of chromosome
mutations
animations of the 6 structural mutations
The mutations
deletion..... 
acentric fragment is lost
Cat cry karyotype (not on web) CriDuChat.gif
"Cri-du-chat syndrome was first described by Lejeune et
al. (1963) as a hereditary congenital syndrome associated with
deletion of part of the short arm of chromosome 5. The deletions
can vary in size from extremely small and involving only band 5p15.2
to the entire short arm. Although the majority of deletions arise
as new mutations, approximately 12% result from unbalanced segregation
of translocations or recombination involving a pericentric
inversion in one of the parents." "The cri-du-chat syndrome
appears to be one of the most common human deletion syndromes, with
an incidence varying between 1 in 20,000 to 1 in 50,000 births (Niebuhr,
1978). The frequency in populations of profoundly retarded patients
(IQ less than 20) is approximately 1% (Niebuhr, 1978)." Ref: OMIM
Duplications
Duplication and Deletion via unequal crossing over ... UnequalXover.gif
Unequal crossing over in Drosophila
Bar eye model unequal x-over
Bar eye polytenes... Fig
21.5
as a source of new genes
Inversions
paracentric inversion (centromere not within inverted
segment)
crossover in loop
sequence...
If a crossover occurs in the loop, the crossover products
will not be recovered in the test cross progeny.
It is as if crossovers were suppressed. Are they
really suppressed?
27 October 2004
complete chapter 21, start on chapter 8
Discussion of chromosome mutation table should be completed this week
in recitation.
There may be some additional items given in recitation.
The importance of knowing about these mutations is evident from the
current issue of the journal Nature
Mulley, J. and P. Holland (2004). "Comparative genomics: small genome,
big insights." Nature 431(7011): 916-7.
Jaillon, O., J. M. Aury, et al. (2004). "Genome duplication in the
teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype."
Nature 431(7011): 946-57.
And, in the same issue of Nature, another completion of the human genome
project
Stein, L. D. (2004). "Human genome: end of the beginning." Nature
431(7011): 915-6.
And, it is good to know about Barbara McClintock, the geneticist who
worked out the details of a lot of the chromosome mutations and later revolutionized
modern genetics.
also, the idea of the bridge, breakage, fusion cycle and the importance
of the telomere.
Effect of crossover within loop Fig 21.7
bridge and fragment... A simple animation of bridge and
fragment.
C of ClB is not true crossover suppression, but the lack of
recombination in male Drosophila certainly
is crossover suppression.
complete paracentric inversion story
if x-over in loop
at anaphase-I: bridge and fragment configuration
at end of meiosis:
from the may apple....... podo9a.JPG
pericentric inversion (centromere within inverted segment)
genotypes (note shift of centromere) ....PeriInversion2.GIF
results of crossover in loop (not on web) .......21.8
between chromosome mutations:
translocation
models for reciprocal translocation (not
showing 4-strandedness; also not showing
chiasmata)
1a.Derivation of translocations
animation
2. Pairing
into quadrivalent at pachytene
3. Adjacent
and alternate segregation (metaphase-I)
4. Adjacent segregation (metaphase-I)
5. Adjacent and to poles (anaphase-I)
6. Adjacent at end of ana-I
7. Alternate segregation (metaphase-I)
8. .Alternate to poles (anaphase-I)
9. Alternate at end of ana-I
10. Adjacent segregation, metaphase-I
11. Alternate, metaphase-I
zig-zag best with pop beads
translocation heterozygote problems
Importance of spindle fiber arrangement and chiasmata
animation of alternate segregation.. TransAnimation.gif
Sometimes the breakage and fusion of the chromosome mutations leads to
the expression of a phenotype, other times not.
Note Philadelphia chromosome in text Figure 21.11, the result of
a reciprocal translocation betwee chromosomes 9 and 22 resulting in leukemia,
now treated with a drug STI-571. There are "at least
94 disease related translocation gene-fusion partners
in neoplastic disorders." Science 291: 1224. Work of
Brian Druker. "I think that STI-571 is one of the most important
validations of the cancer research effort for the past
30 years. We're on the right path to beating cancer."
Chronic Myelogenous Leukemia (CML)
Laboratory studies have shown that Gleevec also inhibits an enzyme called
C-Kit which is present in a relatively rare
form of cancer called GIST (Gastro Intestinal Stromal
Tumor).
translocation causes production of a
novel enzyme: Brc-Abl; a tyrosine kinase, responsible
for uncontrolled mitosis
"STI571 was the best at killing cells
that had Bcr-Abl"
OMIM # 189980: "The t(9;22) translocation
occurs in greater than 90% of chronic myelogeneous leukemia,
25 to 30% of adult and 2 to 10% of childhood acute lymphoblastic
leukemia (ALL; see 159555), and rare cases of acute myelogenous
leukemia. The translocation results in the head-to-tail fusion of
the BCR (151410) and ABL genes (Chissoe et al., 1995)."
Abl = Abeldon murine leukemia viral oncogene OMIM
#189980
Discussion of heterochromatin: Facultative and Constitutive.
(important to know these for next item)
euchromatin and heterochromatin
simple statement: during interphase euchromatin is diffuse
and lightly stained; during interphase
heterochromatin is tightly coiled and stains
darkly.
Robertsonian translocations; a special kind of reciprocal translocation
see text, Fig 21.16
1. Models for formation
1a. The genotypes
2. The chromosomes and pairing
3. Normal and abnormal distribution of chromosomes
21-21 Robertsonian translocation.(not on web). Robertsonian21-21.gif
comparison of mammalian species
15 October 1999 issue of Science; Comparative Genomics Mammalian
Radiations Genome Maps 10
Chromosome number mutations
euploidy (popyploidy; sets of chromosomes)
autoploidy (one species)
autotetraploidy via colchicine
may be fertile or sterile, related to pairing, species
variation
triploidy via double fertilization
Details of euploidy (not for any exam) .. detailseuploidy.htm
alloploidy (more than one species)
allotetraploidy (2n + 2n, two species)
Karpechenko
Karpechenko, Vavilov, Dobzhanksy
photo... Karpechenko.GIF..not
on web
Karpechenko sequence (not on
web, see below)..... ../Karpechenko.html
hexaploid wheat (see text)
aneuploidy (individual chromosomes; 2n + or - chroms)
normal
and abnormal disjunction (see movie page)
idea
of two by two chromosome pairing in meiosis
nondisjunction
first division...
second division.
examples
XYY
Turner Syndrome (XO).
Klinefelter Syndrome (XXY)
Down Syndrome (trisomic 21).
somatic nondisjunction
in formation of a mosaic..
gynandromorph - sexual mosaic, male in portions, female in others
29 October 2004
To complete chapter 21 with some examples
Comparison of X inactivation center in humans and mice. They differ
by the fixation of a single paracentric inversion (not on web).
Comparison of mammalian chromosomes..not on web;.Exhibit 8-37 reduced.gif
Chromosome doubling in evolution for animals
Mulley, J. and P. Holland (2004). "Comparative genomics: small genome, big
insights." Nature 431(7011): 916-7.
the idea: chromosome doubling has occurred in vertebrate evolution;
after the duplication there was a loss of genetic material
Again, this is not new. This was the proposal of Susumu Ohno
based on rough estimates of DNA content in various species.
ploidy super important in evolution in plants
Importance of mutations in agriculture, hexaploid wheat.