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Genetics 1.1 Resume
Genetics 1.1 Resume
SECTION 3. GENETICS.
He used the symbols for the explanation of his results. The dominant character he
indicated by the capital latter (A), the recessive character – be the small letter (a).
The symbol of female genotype is ♀, the symbol of male genotype is ♂, the
symbol of cross – x. Parental lines – capital letter P, the gametes – G, the first filial
generation – F1, the second filial generation – F2.
P (Parents): ♂ AA x ♀ aa
mark of male mark of female
individual individual
MEIOSIS
G (Reproductive A a
Cells):
F1 (Zygotes): Aa
P1: ♂ Aa x ♀ Aa
G: a A A a
F2: AA : Aa : Aa : aa
homo- hetero- homozygous
Similar results were obtained when Mendel crossed plants of six other pairs of al-
ternative characteristics. Mendel concluded that the traits from the parental lines were
transmitted as two different elements of a particulate nature that retained their purity
in the hybrids. We called the element associated with the trait seen in the hybrids
11
(yellow seeds, used in the example) dominant, and the other element, associated with
the trait not seen in the hybrids but seen in their progeny (green seeds), recessive.
Mendel's conclusions were reinforced by the results of experiments in which F 3
progeny produced by the self-pollination of individual F2 plants were observed. In the
experiment with yellow versus green, for example, F2 plants grown from green seeds
produced only green F3 seeds. When 565 F2 plants were grown from yellow seeds,
193 of them produced yellow seeds but the other 372 plants produced both yellow
and green seeds in a proportion very close to 3 to 1 the results can be diagrammed
as follows:
F 2 yellow plants (565 were tasted):
1/3 (193) - gave plants producing only yellow F3 seeds
2/3 (or 372) - gave plants producing both yellow and green seeds;
- 3/4 were with yellow seeds;
- 1/4 were with green seeds;
Phenotypic ratio F3 seeds is 3:1
F 2 green plants:
All plants with - all gave plants producing only green F 3 seeds
green seeds
The ratio 1:2:1 was observed each time in progeny from F 42 plants. Mendel
formulated the following simple explanation of the 1:2:1 ratio in F2:
1. A pea plant has two hereditary determinants for each observed trait.
2. Each reproductive cell (gamete) of a plant has only one of the two determi-
nants. The two determinants of the pair occur with equal frequencies in the reproduc-
tive cells.
3. The union of male and female reproductive cells in the formation of new zy-
gotes is a random process. If is shown in the figure. We use the symbols A and a to
represent the dominant and recessive determinants.
Using the results of the experiments with pea plants, differed by one pair of al-
ternative characters, Gregor Mendel postulated the principles (laws) of inheritance.
2. Law of Purity of gametes: During the formation of gametes the paired char-
12
acteristics (genes) separate and segregate at random so that each gamete re-
cessive one or other characteristics (alleles).
The unit characters or hereditary units are transmitted to their off springs
through gametes. During reproduction parents produce gametes which contain all the
genes for all the characters of an organism. However, these genes are present in sin-
gle doses. For example-pea plant may have hundreds of morphological and physio-
logical characters. Among them, if we choose one character, then it is controlled by a
particular pair of allelic genes. During reproduction only one gene enters into one
gamete, thus gametes contain only one gene for this character. Thus the gamete is
considered as pure and uncontaminated with respect to the said character. The same
principle holds good for other characters also.
3. The Principle of Uniformity (Principle of Dominance): The hybrids of
cross between the pure line organisms are uniformity in genotype and phenotype.
4. The Principle of Segregation: The segregation of characters of F2 hybrids
in the complete dominant inheritance is occurred in the definite quantitative propor-
tions.
Cytological basis of the Principle of Uniformity.
Characters:
A – yellow colour of seeds;
a - green color of seeds;
P: ♂ AA x ♀ aa
Yellow Green
G: A a
F1: Aa
100% yellow
P1: ♂ Aa x ♀ Aa
yellow yellow
G: a A A a
F2: AA : Aa : Aa : aa
Genotypic ratio: 1 2 1
Phenotypic ratio: 3 yellow : 1 green
13
Dihybrid cross – is the cross between the organisms which differed by two char-
acters.
After the monohybrid cross, Mendel crossed the parental plants that differed in
two or three pairs of alleles with different characteristics. For example, plants from a
true-breeding line having round seeds which were yellow were crossed with plants
with wrinkled green seeds. The F1 seeds from this cross were round and yellow, so
they were hybrids for either characters, or dihybrid. This phenotype was expected
from the results of the individual monohybrid crosses. Round seed shape and yellow
color were dominant. The F2 seeds had four possible combinations of phenotypic
characteristics:
9/16 round, yellow 3/16 wrinkled, yellow
3/16 round, green 1/16 wrinkled, green
Mendel also noticed that four phenotypes in the F2 from the dihybrid cross oc-
curred approximately in the proportions 9/16 round and yellow; 3/16 wrinkled and
yellow; 3/16 round and green; 1/16 wrinkled and green. Similar 9:3:3:1 ratio of F2
phenotypes were found in the progeny of other dihybrid crosses.
So, Mendel formulated The Principle of Independent Assortment: Inher-
itance of pairs of characters located in the different chromosomes is independently
from each other.
Cytological basis of the Principle of Independent Assortment .
Gametes: AB ab
F1 progeny: AaBb
round, yellow
AB Ab aB ab AB Ab aB ab
F2:
♂ AB Ab aB ab
♀
AB AABB AABb AaBB AaBb
Ab AABb Aabb AaBa Aabb
aB AaBB AaBb aaBB aaBb
ab AaBb Aabb aaBb aabb
14
F2 progeny: Genotypes Phenotypes
1/16 AABB + 2/16 AABb +
2/16 AaBB + 4/16 AaBb = 9/16 round, yellow
Risks to children:
1. When only one parent is affected, Fig. 3.2. Autosomal dominant type of
every child he/she has a 50% chance to be af- inheritance.
fected and a 50% chance to be unaffected.
19
2. When both parents are affected, every child they have has a 75% chance to
be affected, and a 25% chance to not be affected. Of note, in some conditions having
two damaged copies of the gene is too severe and may not be compatible with life.
Examples of disorders with autosomo-dominant type of inheritance.
- Antithrombin III deficiency;
- Familial
hypercholesterolaemia;
- Huntington's disease;
- Myotonic dystrophy;
- Neurofibromatosis Type I
(von Recklinghausen's disease)
- Osteogenesis imperfecta;
- Achondroplasia;
- Brachydactyly;
- Hypertrichosis; Fig. 3.3. Pedigree, analyzing the Autosomal
- Skin aplasia; dominant type of inheritance.
- Marfan syndrome.
The year 1865 was marked by two profound biological breakthroughs: Mendel's
publication of his experiments in plant hybridization, and Darwin's provisional hy-
pothesis of pangenesis. Although neither man had any direct evidence for the theo-
ries he proposed, Mendel speculated that cells contained some type of factor that car-
ried traits from one generation to the next, while Darwin proposed that traits could be
passed down via units he termed "gemmules," which he believed traveled from every
body part to the sexual organs, where they were stored (Benson, 2001). Because these
first attempts to explain the mechanisms of heredity lacked any scientific support,
their profound importance went unrecognized by the scientific community for dec-
ades. Nonetheless, Mendel and Darwin's work laid the foundation for formulating a
testable, research-based theory of heredity.
Theodor Boveri Links Chromosomes and Heredity. The end of the nineteenth
century was marked by advancements in cytological techniques and microscopy.
During this period, German embryologist Theodor Boveri took Flemming's findings
to the next level by providing the first evidence that chromosomes of germ cell line-
age provide continuity between generations. Boveri found evidence for this hypothe-
sis through his research of early development in the roundworm species Ascaris
megalocephala (now known as Parascaris equorum). Ascaris embryos provided an
excellent experimental model for Boveri's observations; this is because the large,
clear cells of the Ascaris embryo have only two pairs of chromosomes, and the em-
bryos develop distinct somatic cell and germ cell lineages during the first few cleav-
age divisions. Boveri was thus able to trace the fate of the chromosomes in individual
cell lineages with great precision, and he made the surprising observation that the full
complement of chromosomes was retained only in the Ascaris germ cell lineage, the
source of future gametes. By contrast, the chromosomes in somatic cells, the source
of all other adult tissues, underwent a curious process of fragmentation and elimina-
tion known as chromosome diminution (chromosome diminution does not occur in
mammals).
Boveri also recognized that chromosome number was reduced in the gametes. In
Ascaris does not occur until fertilization is complete eggs, meiosis, so Boveri was
able to observe the behavior of egg and sperm chromosomes following fertilization.
He noted that Ascaris eggs retained only two chromosomes after the polar body
formed, and that the normal number of four chromosomes was restored following fu-
sion of the sperm and egg pronuclei. Boveri's work provided one of the first descrip-
tions of meiosis.
27
Walter Sutton Finds Evidence for Mendel's Principles. Working independently
near the dawn of the twentieth century, American graduate student Walter Sutton
confirmed and expanded upon Boveri's observations using a superior cytological
model. Sutton, a Kansas farm boy, had made the serendipitous discovery that it was
possible to distinguish individual chromosomes in cells undergoing meiosis in the
testes of the lubber grasshopper, Brachystola magna. Thus, in his classic paper pub-
lished in 1902, Sutton described the configurations of individual chromosomes in
cells at various stages of meiosis. Sutton was able to identify 11 pairs of chromo-
somes that could be distinguished by their sizes, as well as an accessory singleton
that he correctly presumed to be a sex chromosome. Due to its apparent lack of a
partner, this chromosome sorted into only half of the sperm cells, while the remaining
half never received a copy. Though the accessory chromosome was unpaired, it still
replicated and entered stages of mitosis in the same manner as all other chromo-
somes, which prompted Sutton to declare it a "true chromosome" and not simply an
accessory.
Sutton postulated that all chromosomes have a stable structure, or "individuali-
ty," that is maintained between generations, and he used this property to follow the
behavior of individual chromosomes through the various stages of meiosis, including
synapsis. Most notably, Sutton recognized that his observations were consistent with
the, whose findings had only recently been rediscovered. In fact, Sutton closed his
1902 paper with the statement, "I may finally call attention to the probability that the
association of paternal and maternal chromosomes in pairs and their subsequent sepa-
ration during the reducing division as indicated above may constitute the physical ba-
sis of the Mendelian law of heredity." With these words, Sutton articulated the chro-
mosomal theory of inheritance.
Sutton subsequently went on to explain the basis for the ongoing variation among
heritable traits. He noted that the position of each chromosome at the midline during
metaphase was random, and that there was never a consistent maternal or paternal
side of the cell division. Each chromosome was, therefore, independent of the others.
When they separated into gametes, the set of chromosomes in each daughter cell
could contain a mixture of the parental traits, but not necessarily the same mixture as
that of other daughter cells. The newly discovered chromosomal independence during
meiosis meant that the number of possible chromosomal combinations for each gam-
ete could be calculated based on the number of chromosomes in the organism: specif-
ically, there are 2n possible combinations of chromosomes in gametes, with "n" repre-
senting the number of chromosomes in the gamete. Furthermore, considering all the
possible pairings of one gamete with another, the variation in zygotes is (2n)2, which
results in some fairly large numbers. Indeed, Sutton provided examples of the poten-
tial variation among hypothetical organisms with gamete chromosome numbers rang-
ing from 1 to 19.He also correctly assumed that there was more than one trait present
on each chromosome, so the actual total variation was even higher than any of those
included in the table.
This observation of potential variation added strength to Sutton's assertion that he
had discovered the physical basis for Mendel's principle of independent assortment.
28
Still lacking, however, was definite proof. Scientists thus needed an experimental
system in which the inheritance of genetic traits could be linked directly to the behav-
ior of chromosomes. Such an opportunity presented itself soon thereafter, with a dis-
tinct mutation in the fruit fly Drosophila melanogaster.
F2 in sex: 2 ♀ : 1♂ : 1♂
F2 phenotype: 3 Red : 1 White
In the reciprocal cross, a white-eyed female crossed with a red-eyed male pro-
duced of F1 red-eyed females and white-eyed males. Inbreeding these F1 flies pro-
duced equal numbers red-eyed females, red-eyed males and white-eyed males, white-
eyed females (fig. 4.3).
F2 in sex: 1 ♀ : 1♂ : 1♀: 1♂
From this Morgan rightly concluded that only the X chromosome carries the
gene for eye color. There is no gene locus for eye color on the Y chromosome. This
phenomenon is known as sex linkage.
XW – Red
Xw – White
Parental lines: ♀ XW XW x ♂ Xw Y
W w
G: X X Y
F1 in sex : ♀ XW Xw ♂ XW Y
P1: X W Xw x ♂ XW Y
W w W
G: X X X Y
F2 in sex: 1 ♀ XW XW : 1♀ XW Xw : 1 ♂ XW Y : 1 ♂Xw Y
Reciprocal cross:
Parental lines: ♀ X w Xw x ♂ XW Y
w W
G: X X Y
F1 generation: 1 ♀ XW X w : 1 ♂ Xw Y
Red White
P1: ♀ XW Xw x ♂ Xw Y
W w w Y
G: X X X
F2 in sex: 1 ♀ XW Xw : 1♂ XW Y : 1 ♀ X w Xw : 1 ♂ X w Y
F1 generation: B b
V v
V v v v
Grey Long Black Vestigial
F1: B b : b b
V v v v
Grey Long Black Vestigial
50% 50%
The results of two crosses convince that development of analyzing signs is con-
trolled by different genes localized in one chromosome.
Cross of female-hybrid of F1 with black male with rudimentary wings (test cross
II) gives 4 variants of individuals.
They have combinations of signs which are formed in independent inheritance,
but quantitative correlation of hybrids is another.
TEST CROSS II:
P1: ♀ B b x ♂ b b
V v v v
Grey Long Black Vestigial
F1: B b b b B b b b
V v v v v v V v
This result shows the partial linkage of hereditary signs and breach of linkage is
explained by crossing over.
The comparison of results of the second (female-hybrid in the cross) and the first
(male-hybrid in the cross) experiments testifies to possibility of incomplete and com-
plete linked inheritance of one pair of signs.
This opposition is explained by peculiarity of biology of fruit-fly which is in-
cluded in absentee of crossing over in gametogenesis of males.
37
In own example quantity of offspring with changed correlation of sings (such in-
dividuals are called crossovers) and therefore controlling alleles form 17%. This fig-
ure indicates the number of crossing-over gametes. Other combinations of genes of
fruit-fly differ from by other frequency of crossing over. In the constant conditions
(temperature, age of female and other) this value is constant for every pair of genes of
one chromosome. For example, the number of crossing-over gametes for genes of
white eyes and yellow color of body is 1,5%; for genes of yellow body and rudimen-
tary wings is 47%. Power of gene linkage is inversely proportional to the distance be-
tween them in chromosome (this is the rule, or the law of Th. Morgan).
Constancy of percentage of crossing-over between the genes is used as index of
relative distance between them and order of inter disposition during composition of
chromosome maps. The unit of distance between the genes is called morganid. It
corresponds to the distance by which crossing over takes place in 1% of gametes.
At the distance of 50 morganids and more over signs are inherited independently
in spite of localization of genes in one chromosome.
C? A B C?
4
9 9
2) Examine the next largest COV, that is R - S = 8%, and insert both possible po-
sitions of R on the chromosome, relative to S.
R? S P R?
8 6
8
3) Repeat the procedure for the next largest COV, that is R -P = 14%. This indi-
cates that the right-hand position of R is incorrect.
R S P
8 6
14
4) Repeat the procedure for the COV for P - Q = 24%. The position of Q cannot
be ascertained without additional information.
Q? R S P Q?
24 24
If, for example, the COV for Q - R = 10% this would confirm the left-hand posi-
tion for gene Q.
A problem which arises in preparing chromosome maps is that of double crosso-
ver, particularly when considering genes which are widely separated, since the num-
ber of apparent crossovers will be less than the actual number. For example, if cross-
overs occur between alleles A and B and B and C, A and C will still appear linked,
but the chromosome will not carry the recessive allele b.
40
Chromosome mapping involves techniques used to assign a gene or DNA se-
quence to a specific chromosome or a particular region of a chromosome.
41
CHAPTER 6. EXTRANUCLEAR INHERITANCE.
Extranuclear inheritance is the transmission of genes that occur outside the
nucleus. It is found in most eukaryotes and is commonly known to occur in
cytoplasmic organelles such as mitochondria and chloroplasts or from cellular
parasites like viruses or bacteria. It’s also called cytoplasmic inheritance (tab. 6.1).
Table 6.1.
The cytoplasmic inheritance.
Prokaryotes Eukaryotes
Characters
7.2. Biotechnology.
Biotechnology is technology based on biology - biotechnology harnesses cellu-
lar and biomolecular processes to develop technologies and products that help im-
prove our lives and the health of our planet. We have used the biological processes of
microorganisms for more than 6,000 years to make useful food products, such as
bread and cheese, and to preserve dairy products.
Modern biotechnology provides breakthrough products and technologies to
combat debilitating and rare diseases, reduce our environmental footprint, feed the
hungry, use less and cleaner energy, and have safer, cleaner and more efficient indus-
trial manufacturing processes.
Currently, there are more than 250 biotechnology health care products and vac-
cines available to patients, many for previously untreatable diseases. More than 13.3
44
million farmers around the world use agricultural biotechnology to increase yields,
prevent damage from insects and pests and reduce farming's impact on the environ-
ment. And more than 50 biorefineries are being built across North America to test
and refine technologies to produce biofuels and chemicals from renewable biomass,
which can help reduce greenhouse gas emissions.
Recent advances in biotechnology are helping us prepare for and meet society’s
most pressing challenges.
Biotech is helping to heal the world by harnessing nature's own toolbox and us-
ing our own genetic makeup to heal and guide lines of research by:
1) Reducing rates of infectious disease;
2) Saving millions of children's lives;
3) Changing the odds of serious, life-threatening conditions affecting millions
around the world;
4) Tailoring treatments to individuals to minimize health risks and side effects;
5) Creating more precise tools for disease detection; and
6) Combating serious illnesses and everyday threats confronting the developing
world.
Biotech uses biological processes such as fermentation and harnesses biocata-
lysts such as enzymes, yeast, and other microbes to become microscopic manufactur-
ing plants. Biotech is helping to fuel the world by:
1. Streamlining the steps in chemical manufacturing processes by 80% or more;
2. Lowering the temperature for cleaning clothes and potentially saving $4.1
billion annually;
3. Improving manufacturing process efficiency to save 50% or more on operat-
ing costs;
4. Reducing use of and reliance on petrochemicals;
5. Using biofuels to cut greenhouse gas emissions by 52% or more;
6. Decreasing water usage and waste generation; and
7. Tapping into the full potential of traditional biomass waste products.
Biotech improves crop insect resistance, enhances crop herbicide tolerance and
facilitates the use of more environmentally sustainable farming practices. Biotech is
helping to feed the world by:
1. Generating higher crop yields with fewer inputs;
2. Lowering volumes of agricultural chemicals required by crops-limiting the
run-off of these products into the environment;
3. Using biotech crops that need fewer applications of pesticides and that allow
farmers to reduce tilling farmland;
4. Developing crops with enhanced nutrition profiles that solve vitamin and nu-
trient deficiencies;
5. Producing foods free of allergens and toxins such as mycotoxin; and
6. Improving food and crop oil content to help improve cardiovascular health.
45
CHPATER 8. GENOTYPE AS INTEGRATIVE GENETIC SYSTEM OF
AN ORGANISM.
Soon after the rediscovery of Mendel's laws in 1900 there were reports of an in-
heritance pattern that differed from those established by Mendel. The variations were:
1) The degree of dominance differed and incomplete dominance was observed
in certain cases.
2) Various genes were found to possess more than two alleles, or multiple allelic
inheritance was observed.
3) It was found that a trait is governed by the interaction of the interaction of
two or more genes.
This result in F2 phenotypic ratios deviating from the typical Mendelian ratios.
Such variations indicated that Mendel's laws do not apply universally to all sexually
reproducing organisms. There were attempts to explain such a phenomenon by many
researches including Bateson and Punnet. They described genes not as separate ele-
ments producing distinct phenotypes as postulated by Mendel but as producing prod-
ucts which could interact in a predictable way to produce new phenotypic expres-
sions. Depending upon the form of interaction Mendelian phenotypic ratios is modi-
fied in various ways.
For example, if gene A produces a product A resulting in A phenotype and gene
B produces another product B, an organism with genotype AB might show a third
phenotype, different from the one produced by alleles A and B separately.
Today we'll make out some of the important cases of gene interaction resulting
in variations in inheritance patterns.
P: ♂ AA x ♀ aa
Red White
G: A a
F1: Aa
100% pink
P1: ♂ Aa x ♀ Aa
Pink Pink
G: a A A a
F2: AA : Aa : Aa : aa
Genotypic ratio: 1 2 1
Phenotypic ratio: 1 red 2 pink : 1 white
8.1.1. Overdominance.
The condition of a heterozygote having a phenotype that is more pronounced or
better adapted than that of either homozygote. The overdominance is the main cause
for the fitness advantages of heterosis, and then there should be an over-expression of
certain genes in the heterozygous offspring compared to the homozygous parents.
G: IA I0 IB I0
Genotypic ratio: 1 : 1 : 1 : 1
Phenotypic ratio: 1 : 1 : 1 : 1
G: CB cb
G: CB Cb cB cb CB Cb cB cb
49
Recessive epistasis.
A - dominant allele of zonal distribution of pigment in the hair length in mice
(accumulation of pigment in base or end of hair) – grey colour;
a - recessive allele which is not determine the zonal distribution of pigment –
agouti colour;
C - the allele of synthesis of pigment;
c - the absence of pigment (or albinism); gene c doesn't give the possibility to
show itself gene A (a).
agouti mouse white mouse
P: aaCC x AAcc
G: aC Ac
G: AC Ac aC ac AC Ac aC ac
50
8.3.2. Complementary.
The next example of departure from Mendelian ratios is complementation (the
complementary interaction of dominant alleles of genes).
The first example of complementation
(Complementary interaction of dominant non-allelic genes).
A - allele being responsible for synthesis of propigment in sweet pea plant;
a - absence of propigment;
51
B - allele being responsible for synthesis of enzyme which catalyzes the
transmutation of propigment to pigment.
b - absence of this enzyme.
A_bb - white flowers;
aaB_ - white flowers;
aabb - white flowers
A_B_ - purple flowers.
white white
P: AAbb x aaBB
G: Ab aB
G: AB Ab aB ab AB Ab aB ab
G: Ab aB
b b
F1: AaBb - disk-like form
G: AB Ab aB ab AB Ab aB ab
b b b b b b b b
F2: 9 A_B_ : 3 A_bb : 3 aaB_ : 1 aabb
disk-like globe-shaped long
blue x yellow
P: AAbb x aaBB
G: Ab aB
b b
F1: AaBb - all green.
8.3.3. Polymery.
And at last some words about additive interaction of genes (phenomenon of
polymery or polymeric genes). It consists in two or more genes of dominant alleles
controlling the development of one sign in the same degree. These genes are called
polymeric or polygenes and marked the same letter in Latin with figure indexes.
The first example in polymery.
A1 A2 - red colour of wheat grain;
a1 a2 - absence of colour.
54
P: red x white
A1 A1 A 2 A2 x a1 a1 a2 a2
G: A 1 A2 a1 a2
F1: A1a1A2a2 - all brown.
P2: A1 a1 A2 a2 x A1 a1 A2 a2
F2: 9 A1_ A2_ : 3 A1_a2 a2 : 3 a1 a1 A2_ : 1 a1 a1 a2 a2
15 coloured 1 non-coloured.
G P1P2P3P4
p1p2p3p4
F1: P1 p1 P2 p2 P3 p3 P4 p4
mulatto
The distribution in intensivity of skin pigmentation in progeny of mulatto - tet-
raheterozygotes are very large. The intensivity of skin pigmentation in man depends
on number of dominant genes in genotype.
There are inherited with polymeric genes: height, weight, body-building and
mental abilities in man.
8.4. Pleiotropy.
During his study of inheritance in pea plants, Gregor Mendel made several inter-
esting observations regarding the color of various plant components. Specifically,
Mendel noticed that plants with colored seed coats always had colored flowers and
colored leaf axils. (Axils are the parts of the plant that attach leaves to stems.) Mendel
also observed that pea plants with colorless seed coats always had white flowers and
55
no pigmentation on their axils. In other words, in Mendel's pea plants, seed coat color
was always associated with specific flower and axil colors.
Today, we know that Mendel's observations were the result of pleiotropy, or the
phenomenon in which a single gene contributes to multiple phenotypic traits. In this
case, the seed coat color gene, denoted a, was not only responsible for seed coat col-
or, but also for flower and axil pigmentation (Fairbanks & Rytting, 2001).
The term pleiotropy is derived from the Greek words pleio, which means
"many," and tropic, which means "affecting." Genes that affect multiple, apparently
unrelated, phenotypes are thus called pleiotropic genes (Figure 1). Pleiotropy should
not be confused with polygenic traits, in which multiple genes converge to result in a
single phenotype.
Examples of Pleiotropy. In some instances of pleiotropy, the influence of the
single gene may be direct. For example, if a mouse is born blind due to any number
of single-gene traits (Chang et al., 2002), it is not surprising that this mouse would
also do poorly in visual learning tasks. In other instances, however, a single gene
might be involved in multiple pathways. For instance, consider the amino acid tyro-
sine. This substance is needed for general protein synthesis, and it is also a precursor
for several neurotransmitters (e.g., dopamine, norepinephrine), the hormone
thyroxine, and the pigment melanin. Thus, mutations in any one of the genes that af-
fect tyrosine synthesis or metabolism may affect multiple body systems. These and
other instances in which a single gene affects multiple systems and therefore has
widespread phenotypic effects are referred to as indirect or secondary pleiotropy
(Grüneberg, 1938; Hodgkin, 1998).
Pleiotropy in Humans. As touched upon earlier in this article, there are many
examples of pleiotropic genes in humans, some of which are associated with disease.
For instance, Marfan syndrome is a disorder in humans in which one gene is respon-
sible for a constellation of symptoms, including thinness, joint hypermobility, limb
elongation, lens dislocation, and increased susceptibility to heart disease. Similarly,
mutations in the gene that codes for transcription factor TBX5 cause the cardiac and
limb defects of Holt-Oram syndrome, while mutation of the gene that codes for DNA
damage repair protein NBS1 leads to microcephaly, immunodeficiency, and cancer
predisposition in Nijmegen breakage syndrome.
One of the most widely cited examples of pleiotropy in humans is phenylketonu-
ria (PKU). This disorder is caused by a deficiency of the enzyme phenylalanine hy-
droxylase, which is necessary to convert the essential amino acid phenylalanine to ty-
rosine. A defect in the single gene that codes for this enzyme therefore results in the
multiple phenotypes associated with PKU, including mental retardation, eczema, and
pigment defects that make affected individuals lighter skinned (Paul, 2000).
The phenotypic effects that single genes may impose in multiple systems often
give us insight into the biological function of specific genes. Pleiotropic genes can
also provide us valuable information regarding the evolution of different genes and
gene families, as genes are "co-opted" for new purposes beyond what is believed to
be their original function (Hodgkin, 1998). Quite simply, pleiotropy reflects the fact
56
that most proteins have multiple roles in distinct cell types; thus, any genetic change
that alters gene expression or function can potentially have wide-ranging effects in a
variety of tissues.
CHPATER 9. VARIABILITY.
WINTER SUMMER
Norm of reaction
The repair mechanisms are the result of biological adaptation during the evolu-
tionary process. If repair mechanism did not exist, there would not have been any life
on the earth which is being constantly exposed to sunlight and gaseous pollutants.
Pho-toreactivation seems to be the first developed repair mechanism followed by the
excision and the post-replication repair mechanisms. More than one repair system en-
sures the neutralization on harmful effects of UV and other mutagens. In case one
mechanism fails, the other can take over.
Two affected individuals are present among the offspring of unaffected parents.
In such a situation a reasonable interpretation is that both parents carry the determin-
71
ing allele (they are both heterozygous) and that the trait of interest is determined by
the homozygousity of the recessive allele.
A pedigree is not always interpretable, for example, the one in panel.
Since one parent carries the trait, there are two possibilities: 1) the affected fa-
ther is homozygous recessive, the mother is heterozygous, and the trait is inherited as
a homozygous recessive, or 2) the affected father is heterozygous, the mother is ho-
mozygous recessive, and the trait is inherited as a dominant.
Pedigree analysis in humans is frequently concerned with traits, such as albi-
nism, that are quite rare in the population. Thus it is quit unlikely that both parents
would carry the determining allele. The recessive inheritance of a rare condition is
indicated by several features of a pedigree. Specifically, the trait usually does not ap-
pear in every generation, it may reappear in a family after being absent in several
previous generations.
Children with the trait usually will have phenotypically normal parents, who
must therefore be heterozygous. Such a parent is often termed a carrier. As expected
from the pedigree 1 albinism is inherited as a recessive. In the infrequent case in
which both parents are affected, all of their offspring will be affected.
If a rare trait is inherited as a dominant, most affected individuals will be hetero-
zygous. Most matting of these individuals will be with homozygous recessive par-
ents and result in about equal numbers of affected and normal offspring. Thus, the
trait will appear in every generation, though some lines of descent may lack the trait
if by chance only normal offspring occur. In the case of dominant inheritance, the
trait will never be seen among the offspring of normal parents.
In the next generation, each of the three paternal genotypes can mate with each
of the three maternal genotypes. Thus the frequency of each genotype (AA, Aa and
aa), is stable over successive generation and the population is said to be in Hardy-
Weinberg equilibrium.
Of course, this principle depends upon certain assumptions of ideal population:
1. Mating in random.
2. Allele frequencies are the same in males and females.
3. The genotypes are all equal in viability and fertility (that is selection does not
occur).
4. Mutation does not occur.
5. Migration into population does not occur.
6. The population is sufficiently large that the frequencies of alleles will not
change from generation because of chance.
The most important medical application of the Hardy- Weinberg equilibrium
is the determination of allele frequency and heterozygote carrier frequency in a
population for which the frequency of a trait is known.
For example, cystic fibrosis occurs in approximately 1/2000 whites of Northern
and central European origin. Thus q2, or the frequency of homozygous affected indi-
viduals, is 1/2000, and q/ the frequency of the mutant allele is 2000 = 1/45 or 0.022.
The frequency of the normal allele is p = (1-q) = 44/45 or 0,978. The heterozygote
carries frequency is 2pq = 2x 44/45 x 1/45 = 1/23 or 0,044. Thus, more than 4% of
whites are heterozygous for the cystic fibrosis allele, and fact of considerable im-
portance in genetic counseling of families with cystic fibrosis.
73
Neurofibromatosis is characterized by
variable expression, pleiotropy and heterogeneity
which are both allelic and non-allelic. The dis-
covery of the NF1 gene has shed light on tumour
formation both in NF1 and in general.
The neurofibromatoses are genetic disor-
ders that cause tumors to grow in the nervous
system. Frequency is 1 in every 3,000–4,000
live births; type of inheritance is autosome-
dominant.
LLisch nodules
The tumors begin in the supporting cells that make up the nerves and the mye-
lin sheath - the thin membrane that envelops and protects the nerves. These disorders
cause tumors to grow on nerves and produce other abnormalities such as skin changes
and bone deformities. Although many affected persons inherit the disorder, between
77
30 and 50 percent of new cases arise spontaneously through mutation in an individu-
al's genes. Once this change has taken place, the mutant gene can be passed on to
succeeding generations. Scientists have classified the disorders as neurofibromatosis
type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis, a type that was
once considered to be a variation of NF2. NF1 is the more common type of the
neurofibromatoses. In diagnosing NF1, a physician looks for changes in skin appear-
ance, tumors, or bone abnormalities, and/or a parent, sibling, or child with NF1.
Symptoms of NF1, which may be evident at birth and nearly always by the
time the child is 10 years old, may include light brown spots on the ski ("cafe-au-lait"
spots), two or more growths on the iris of the eye, a tumor on the optic nerve, a larger
than normal head circumference, and abnormal development of the spine, a skull
bone, or the tibia.
NF2 is less common and is characterized by slow-growing tumors on the
eighth cranial nerves. The tumors cause pressure damage to neighboring nerves. To
determine whether an individual has NF2, a physician looks for eighth nerve tumors,
cataracts at an early age or changes in the retina that may affect vision, other nervous
system tumors and similar signs and symptoms in a parent, sibling, or child.
The distinctive feature of schwannomatosis is the development of multiple
schwannomas (tumors made up of certain cells) everywhere in the body except on the
vestibular branch of the 8th cranial nerve. The dominant symptom is pain, which de-
velops as a schwannoma enlarges or compresses nerves or adjacent tissue. Some
people may develop numbness, tingling, or weakness in the fingers and toes.
Clubbing of the fingersin a person with cystic fibrosis The scheme of mucus blockage
This was, in fact, the first genetic disorder in humans shown to be due to a specific
enzyme defect by Jervis in 1953. As a result of the enzyme defect, phenylalanine ac-
cumulates and some is converted into phenylpyruvic acid and other metabolites
which are excreted in the urine. The enzyme block leads to a deficiency of tyrosine
with a consequent reduction in melanin formation. Affected children therefore often
have blond hair and blue eyes and areas of the brain which are usually pigmented,
e.g., the substantia nigra, can also lack pigment.
Treatment. Bickel suggested that phenylalanine could be removed from the diet,
which has proved to be an effective treatment. If PKU is detected early enough in
childhood, mental retardation can be prevented by giving a diet containing a re-
stricted amount of phenylalanine. Phenylalanine is, however, an essential amino acid
and therefore cannot be entirely removed from the diet. By monitoring the level of
80
phenylalanine in the blood, it is possible to supply sufficient amounts to meet normal
requirements and avoid levels which result in mental retardation.
Diagnosis. (Screening programs). PKU can be screened for by tests which de-
tect the presence of the
metabolite of phenylal-
anine, phenylpyruvic
acid, in the urine by its
reaction with ferric
chloride or through ele-
vated levels of phenyl-
alanine in the blood in
the Guthrie test. The
latter test involves tak-
ing blood samples from
children in the first
week of life and com-
paring the amount of
growth induced by the
sample with standards
in a strain of the bacte-
ria Bacillus subtilis
which requires phenylalanine for growth. This technique has been replaced in most
centers by use of direct fluorescent or immunological assays of phenylalanine levels.
Galactosemia is a rare disorder that affects the body's ability to break down a
food sugar called galactose (found in milk and other dairy products). Galactosemia
was first discovered in 1908 by the physician Von Ruess.
Normally, the body breaks down lactose into galactose and then into glucose (a
sugar used for energy). People with galactosemia are missing an enzyme called
GATL (galactose-1-phosphate uridyl transferase), which normally converts galactose
into glucose. Without this enzyme, harmful amounts of galactose build up in the
blood.
The most common form of the disorder, classic galactosemia, is passed down
in an autosomal recessive pattern. Classical galactosemia affects 1 in every 55,000
newborns.
To get the disorder, a child must inherit one defective gene from each parent.
Inheriting one normal gene and one mutated gene makes a person a carrier. A carrier
produces less of the GALT enzyme than normal, but is still able to break down glu-
cose and avoid having symptoms of galactosemia. However, carriers can still pass on
the mutated gene to their children.
The build-up of galactose in the body can cause several severe symptoms: kid-
ney failure, an enlarged liver, cataracts (clouding of the eye lens), poor growth, and
mental retardation.
People can inherit a milder form of the disorder when a different gene, also in-
volved in galactose metabolism, is mutated. These patients often suffer from cata-
racts, but not the other symptoms associated with classical galactosemia.
In most countries, babies are tested for galactosemia at birth. Using a tiny
blood sample taken from the baby's heel, the test checks for low levels of the GALT
enzyme. This allows for prompt treatment, which can substantially prevent the seri-
ous symptoms of this disorder.
For those families with a history of the disorder, a doctor can determine during
a woman's pregnancy whether her baby has galactosemia 1) by taking a sample of
fluid from around the fetus (amniocentesis), or 2) by taking a sample of fetal cells
from the placenta (chorionic villus sampling or CVS).
Newborn infants with galactosaemia present with vomiting, lethargy, failure
to thrive and jaundice in the second week of life. If untreated, they go on to develop
complications which include severe mental retardation, cataracts and cirrhosis of the
liver.
Both the Duchenne and Becker forms of muscular dystrophy are associated
with a heart condition called dilated cardiomyopathy. This form of heart disease en-
larges and weakens the heart (cardiac) muscle, preventing it from pumping blood ef-
ficiently. Dilated cardiomyopathy progresses rapidly and is life-threatening in many
cases. In people with Duchenne muscular dystrophy, the signs and symptoms of car-
diomyopathy typically appear in adolescence. The onset of cardiomyopathy in people
with Becker muscular dystrophy is later, usually in early to mid-adulthood.
Ap-
pearance of
patient
with
Klinefelter syndrome Gynecomastia
Karyotype of patient
with Klinefelter syn-
drome:
47,XXY.
(Archives of Kursk re-
gional hospital Medico-
genetical consultation,
2007)
Clinical manifestations
of Klinefelter syndrome
88
Turner syndrome was first described by Turner (1938) in individuals who were
chromatin negative and phenotypically females with 45 (45,X) somatic number of
chromosomes. The frequency is about 1/5000 in liveborn girls.
Clinical manifestations
of Turner syndrome
This is the only total monosomic condition normally compatible with life. Ovar-
ian dysgenesis, primary amenorrhea and fertility are the constant characteristics asso-
ciated with Turner's syndrome. The germ cells and endocrine tissue are completely
absent. Secondary sexual characteristics are also totally absent. The females show
other physical abnormalities like short stature, a short neck with webbing of the skin,
swelling of the hands and feet in infancy, increased carrying angle at the elbow, car-
diovascular and renal abnormalities, high arched palate. The chest is broad with
widely spaced nipples. In spite of these physical abnormalities of various organs, the
nervous system is not affected and the individuals with Turner's syndrome seem to
have normal brain development. They do not have tendencies towards mental retar-
dation.
89
Autosomal abnormalities in man.
A duplication or deficiency of a part or whole of an autosomal chromosome re-
sults in a change in phenotype and is termed as autosomal abnormality. The somatic
chromosomes exist in homologous pairs carrying alleles of a gene at each locus. The
absence of one allele out of the two, when one of the chromosomes is missing, leads
to monosomic condition for that autosomal pair and this condition is lethal in most of
the cases. Similarly, an extra chromosome, a condition called trisomy, also leads to
serious abnormalities. The following conditions are of common occurence and are
social economically important.
Down syndrome. The individuals with Down's syndrome symptoms have 47
chromosomes (47, XX (XY),+21) instead of 46 in their somatic cells. This condition
was first described by Down (1866) and was called “mongolian idiocy” by him. It is
commonly known as “mongolism” because the suffers have a specific phenotypic re-
semblance to the individuals of oriental race, the Mongols.
Down syndrome is due to the presence of an extra chromosome number 21. This
was first demonstrated by Lejeune et al. (1959). Chromosome number 21 is the
smallest autosome in humans. It is present in the form of a complete extra chromo-
some or a major part of it, either free or translocated to another autosome of D or G
groups.
90
The two obvious characteristics of Down’s syndrome are that the inflicted per-
sons are mentally retarded and have characteristic facial resembling mongols. These
persons can be easily detected and diagnosed at birth. The condition of mongolism
occurs in all races and is presumed that the chance of a woman producing a mongol-
oid child than her younger counterparts. The frequency of the syndrome is 1 to 700 –
800 births.
A small and rounded head region with flat back is the most characteristic feature
of this syndrome. If carefully examined, almost every organ is defective in develop-
ment. The nose with a flattened bridge looks underdeveloped. “Epicanthic folds” of
skin and a protruding tongue which is coarsely fissured on the dorsum is another
prominent feature of the syndrome. The size of the external ear varies. It is smaller
or larger than the normal size. The hair on the head is always strait irrespective of the
racial characteristics. The skin is dry and coarse. The suffers are more susceptible to
infections due to low lymphocyte count in the blood. Endocrine glands are
hypoplastic and muscles are hypotonic in most suffers.
Patau syndrome. This syndrome was described by Patau et al.(1960) and is
associated with the trisomy of chromosome number 13 (D-group; 47,
XX(XY),+13).
91
Cleft palate/lip
Polydactyly
Individuals with this abnormality have a small and abnormally shaped head
(microcephaly) with small eyes. Hare lip and cleft palate is very common among the
suffers. Epicanthic folds on the face, a large flat nose, small mandibles and low set
malformed ears are other prominent features of this syndrome. Polydactyly is most
conspicuous. Internal organs show abnormalities. These are cardiovascular
anomalies, polycystic kidney, reduplicated ureters and excess of normal tissue in
liver, kidney, lung, pancreas, etc. The biochemical abnormality is the presence of
fatal haemoglobin at birth. This may be due to delayed development. The life ex-
pectancy is very poor, not more than a year or so.
92
Edward's syndrome. This syndrome was first described by Edward et al.
(1960) and is associated with the trisomy of chromosome number 18 (E-group;
47,XX(XY),+18). Like Patau's syndrome this is also characterised by congenital
anomalies affecting almost all tissues and systems with short life span.
Amniocentesis
During an amniocentesis, a sam-
ple of the amniotic fluid surrounding
the fetus is obtained. This fluid con-
tains cells from the fetus that can be
cultured, or grown, to determine chro-
mosomal make up, fetal lung maturity,
and other information about the fetus.
Amniocentesis carries a risk of fetal-
death of less than 1%, particularly
when performed by skilled practition-
ers.