Lecture 11: Mendelian Genetics I                                                                               pdf _download pdf _download

Review Cell Division....

Comparing    Mitosis    and     Meoisis

        

While meiosis provides the required genetic constancy from generation to generation, as I mentioned, it also provides for a considerable degree of variation in the offspring -without introducing mutations or errors in the distribution of the chromosomes within any of the gametes.

For the sake of completion, as to how and when the male and female gametes develop is both species and sex dependent.

Sometimes, however, the incredible choreography -that is cell division- doesn't always go according to plan.

Nondisjunction is the most commonly occuring error, in ths regard, wherein either homologous chromosomes fail to separate during anaphase I, or sister chromatids fail to separate during anaphase II......resulting in a condition known as aneuploidy.

    

Aneuploidy, results, which can can give rise to a number of genetic abnormalities in the human condition, most of which do not survive past formation of the egg.

Meiosis demonstrates one of the apparent  "truisms" of the living world, "all things biological come in pairs" (Francis Crick), where copies of the genetic information are transferred to the gametes by division of the germ-line cells into four "gametes" (two by two).

Moreover, as we have seen, because of the packaging of DNA in anticipation of cellular division all of these features can be readily observed under the microscope.

Indeed, at the turn of the last century the whole process of the "dancing chromosomes" meiosis2.mov was correllated to the behavior of potential passage of "information" from one generation to the next Sutton and Boveri (1902).

At this time, while the microscope brought incredible insights in to how cells behaved, people's understanding of inheritance had not really changed from the 16th century idea of fully formed "homunculi" present in either the sperm of the father or somewhere within the mother... then, though some understanding of agriculture and obviously inheroted traites the idea of "blending" of parental traits came to the fore around the early 19th century.

 

Curiously, an Augustinian Friar by the name of Gregor Mendel had already finished and published his work almost forty years earlier (in 1865/1866), but no one had taken any notice of this unassuming Friar.

Even so, with 20/20 hindsight, we need not fall into the same trap and so can appreciate his accomplishments.

Mendel had already finished and published his work almost fourty years earlier (in 1865/1866) but no one had taken any notice of the unassuming Friar.

Mendel had many claims to fame, but one of his big contributions to science was that he devised a careful research plan, and used True-breeding plants.

Mendel’s well-organized research allowed him to "observe" and "record" the phenotypic traits of each generation in sufficient quantities to explain -through mathematical analysis- the relative proportions of the different "phenotypes" of the various progeny. Indeed, his paper is recognized today as a model of clarity.

He chose garden peas as his subjects, as they were easily grown and their pollination was easily controlled.
He controlled pollination by manually moving pollen between plants.
ee  ee 

He could also allow the plants to self-pollinate.
Mendel examined varieties of peas for heritable characters and traits for his study.
A character is a feature, such as flower color.


He define a "trait" as being a particular form or a character, eg. white flowers.

Mendel looked for characters that had well-defined, alternative traits and that were true-breeding.


He considered a trait to be "true-breeding" when it was the only trait that occured after many generations of breeding individuals that exhibited that particular trait (we now call it phenotype).

A true-breeding white-flowered plant would have only white-flowered progeny when crossed with others in its strain.

True-breeding plants, when used for crossing with other plants that have an alternative trait, arre called the parental generation, designated P.

The progeny from such a cross are called the first "filial generation", designated "F1".

When F1 individuals are themselves crossed to each other or "self-fertilized", their progeny are designated F2.

His first experiment examined what we now call a monohybrid cross

Mendel crossed true-breeding plants that differed for a given character.
A monohybrid cross involves one (mono) character and different (hybrid) traits.
Pollen from true-breeding pea plants with wrinkled seeds (one trait) was placed on stigmas of true-breeding plants with spherical seeds (another trait).

The F1 seeds were ALL spherical; somehow the wrinkled trait failed to appear at all.

Because the spherical trait appeared to completely MASK the wrinkled trait when two "true-breeding" parental plants are crossed, the spherical trait was called DOMINANT, and the wrinkled trait was called recessive.

But Mendeld didn's stop there. The F1 plants were then allowed to "self-pollinate".

This step defines the genius of Mendel, and is termed the monohybrid cross or an F1 cross.

The progeny, called F2, were examined: 5,474 were spherical and 1,850 were wrinkled.

From his many experiments, Mendel proposed that the units responsible for inheritance were discrete particles, and that they existed within an organism in pairs; that they separated during gamete formation, and that they retained their integrity.

- this defined the particulate theory, which was in sharp contrast to the "blending theory", that was in vogue at the end of the 19th century.

Essentially, Mendel recogized that each pea had two units of inheritance that kept on showing through for each character.

Gregor Mendel's hypotheses:

1. Hereditary determinants are of a particulate nature. Each genetic trait is governed by unit factors , which "hang around" in pairs (or gene pairs) within individual organisms.

2. When two different unit factors governing the same phenotypical trait occur in the same organism, one of the factors is dominant over the other one, which is called the recessive trait.

3. During the formation of gametes the "paired" unit factors separate or segregate randomly so that each gamete receives either one or the other of the two traits, but only one .

4. The union of one gamete from each parent to form a resultant zygote is random with respect to that particular characteristic.

5. During production of gametes, only one of the "pair members" for a given character passes to the gamete.

6. When fertilization occurs, the zygote gets one from each parent, thus restoring the pair.

You can see where we are going with this, but at the time........

Mendel’s units of inheritance are now equivalent to the genetic units or genes.
Different forms of which are called alleles.

Each allele is given a symbol. In the case of wrinkled seeds, "S" might represent smooth and "s" wrinkled.

By a subsequent convention, uppercase always represents the dominant trait (if it is known), while the lowercase represents the recessive.

If Mendel's appreciation of heredtary holds true then "true-breeding" individuals would each have two copies of the same allele.

Wrinkled would be ss. (two copies of same allele = homozygous)
Smooth true-breeding would be SS. (two copies of same allele = homozygous)

However, if this were to be the case, as a consequence of a cross between true-breeding round and true-breeding wrinkled seed plants, the smooth-seeded plant offspring would be Ss, and would not themselves be true-breeding parents for their own offspring, and would be considered to be heterozygous.

The actual composition of any organism's alleles for a gene is its genotype: Ss would, therefore, be a genotype.

When an individual produces gametes, its alleles separate, so that each gamete receives one member of the pair of alleles.

Giving rise to Mendel's first law, the law of segregation.

Mendel's First Law: Two members of a gene pair segregate from each other into the gametes, whereby one half of the gametes carries one of the traits, the other half carries the other.

To analyze how this might come about a turn of the last century, Cambridge Professor (William Punnett) devised, what is now considered to be the Punnett square, which is a simple box-like device that helps us to consider all genetic combinations and can provide clarity by showing the expected frequencies of genotypes.

The Punnett square shows that the genotypes and associated ratios for a monohybrid cross are:1 SS : 2 Ss : 1 ss. even though the "phenotype" of the progeny exhibits a phenotypic ratio of (approximately) 3 smooth to 1 wrinkled.

traits

While it is now known that a gene is a portion of the chromosome that resides at a particular site, called a locus (plural being loci).

remember, Mendel had no knowledge of this or meiosis, which nicely explains his law of segregation. (See Animation)

Mendel verified his hypothesis by performing what is now termed a test cross, which can determine the genotype (heterozygous or homozygous) of an individual that may exhibit a dominant phenotype of a given trait.

It involves crossing the "unknown" individual to a true-breeding recessive or homozygous recessive.

If the unknown is homozygous dominant for the particulat trait what is the outcome?

If the unknown is heterozygous for a given trait, approximately half the progeny will have the dominant trait and half the recessive trait.

Mendel's second law is the law of random assortment and simply states:

Mendel's Second Law: During gamete formation the segregation of one gene pair is independent of all other gene pairs


This second law describes the outcome of a dihybrid (two character) cross, or hybrid cross involving additional characters/traits.

 red ball

A dihybrid is an individual that is a double heterozygote (e.g., with the genotype SsYy).
Mendel’s second law states that the Ss alleles assort into gametes completely independent of the Yy alleles.

Thus, the dihybrid, Ss Yy, produces gametes that have one allele of each gene.

In this cross, Four different gametes are possible and will be produced in equal proportions: SY, Sy, sY, and sy.

Random fertilization of gametes yields the outcome visible in the more complex Punnett square.

Note that it is now 4 x 4 table construction to accommodate 16 possible genotypes.

Filling in the table and adding the like cells reveals a 9:3:3:1 ratio of the four possible phenotypes (smooth yellow, smooth green, wrinkled yellow, and wrinkled green).

Monohybrid crosses, dihybrid crosses -and even more complex- trihybrid crosses: same principles.

 

Know how to test for Mendel's laws.  

While Mendel could not comprehend any of the genetic intricaies that his laws might suggest, his determination of his abstract "unitary" traits had far reaching implications in understanding inheritance of these genetic traits and how they could be inherited.

As we have discussed, each of the "gene variants" that Mendel called "factors" are termed Alleles and ALL variants of a given gene reside at a specific locus on a given chromosome.

Variation in allelic types arise by mutation or change in the DNA sequence.

An allele, therefore, can arise due to a mutation at a given locus, and can be analyzed through classical genetics once that variation has been incorporated

Alleles can be randomly mutatagenized to become a different allele, depending on DNA sequence changes and maintained or lost -again in a random manner- unless acted upon by a selective pressure.

"Wild Type", as we have discussed prevously, is a term used to demonstrate the most common allele/trait of a given population. Again, being the "most common" allele in a population does not always mean that the wild-type allele will be the dominant or "superior" allele.

However, some definition of "normalcy" in the genetic expression of traits does provide an incredible advantage in the understanding of how genes work in the whole organism...

In the early twentieth century, G. H. Shull crossed two varieties of corn, and the yield went from 20 to 80 bushels per acre, thus defining a, now common, agricultural practice to increase production in plants.

This is called either hybrid vigor or heterosis, whereby crossbred strains show superior qualities, and it is a result of the fact that continued genetic "in-breeding" often leads to deleterious traits becoming "fixed" in the gene pool (an aspect we wil address later). The mixing of two strains, therefore, reintroduces a number of selectible traits which can enhance the gene pool of the newly defined strains... Use of such hybridization techniques has been a common agricultural practice ever since -to increase production in crops and broadened to cattle etc...

An hypothesis called overdominance even proposes that the heterozygous condition -in certain important genes- is often considered to be selectively "superior" or have a higher fitness than the presence of either homozygote. This occurs far more frequently in cases where a single trait controls more than one phenotype. Such heterosis, however, would be slightly at odds with Mendel's idea of "independent" traits.

Even so, given the potential of heterosis (cross bred alleles show some qualities superior to their parental counterparts), this would threaten the very crux of Mendel's ideas which are premised on the "particulate" nature of genes, and where one allele in any given gene pair is simply dominant over the other

Perhaps, Mendel wasn't perfect...

No, he wasn't, he was also only observing, NOT deducing. Even so, the fact that we are still talking about him is testament to how much he did get right.

 

EXTENSIONS or Modifications to Mendelian Genetics -tend to vindicate Mendelian Genetics at the genotypic level.

Same basic scheme, but different phenotypical expression......

 

Heterozygotes may show an intermediate phenotype.
For example, red-flowered snap dragons when crossed with white snap dragons will generate pink-flowered plants.\

   gametogenesis gametogenesis

While this phenotype (on the surface) might tend to support the blending theory that Mendel was so avidly trying to overcome, the F2 progeny, of a "selfing" of the pink flowers admirably demonstrates, Mendelian "particulate" genetics, the reason for the change in colour results from a penomenon called "incomplete dominance".

Another example, where Mendelian Genetics apparantly falls down, can be seen in blood types. In this instance, however, Mendel’s laws are also not compromised -at the genetic level.

These blood-types are said to exhibit codominance, where both alleles are expressed. Note that in codominance the phenotype of the heterozygote is completely different (not just a "blend" of the two homozygotic phenotypes).

Mendel made a series of artful choices in choosing traits in peas that "just happened" to be examples of complete dominance

Consequently, Mendel analyzed his "units" in terms of dominant and recessive traits, there are many examples, where variations at a single locus, gives rise to multiple phenotypic effects.

So, let's look a little closer at the behoaviou of genes and their alleles.

Alleles and their Interactions
Differences in alleles of genes are often slight differences in the DNA sequence at the same locus, which result in slightly different products, and can give rise to different phenotypes.

Many "genes" can have "multiple alleles".

A population might have more than two alleles for a given gene, even though only a maximum of TWO can be present in any given "diploid individual".

In rabbits, coat color is determined by one gene with four different alleles. Five different colors result from the combinations of these alleles.

      

Please note, even if more than two alleles exist in a population, any given individual can have no more than two of them: one from the mother and one from the father.

Again, as can be observed, Dominance need not be complete.

Multiple Alleles:The "ABO" blood-type system

The ABO system is now known to be a polymorphism of complex carbohydrate structures of glycoproteins and glycolipids expressed at the surface of red blood cells.

  n      

The alleles for blood type are IA, IBand IO. They all occupy one locus.
These alleles determine which antigens (proteins) are present on the surface of red blood cells.

These "antigens" react with proteins called antibodies in the serum of certain individuals and cause the blood to clot.

 

n    abo1  abo2   abo3

 

The "ABO" blood-type system, however, is not just a series of antigens on the surface of each of red blood cell, but also feature their corresponding "antibodies" that exist within the blood serum.

If A antigen (blood cell) and A antibody (serum) are present in the blood... the blood will clot!!.

Therefore, the result of mixing blood from each of the different ABO blood types can result in red blood cell agglutination, or clumping, which may prove to be fatal.

 

Blood Type Genotypes ABO Enzymes
Present
RBC Antigens
Present
Serum Antibodies
"A"
IA IA, IA IO
"H", "A" A, H
anti-B
"B"
IB IB, IB IO
"H", "B" B, H
anti-A
"AB"
IA IO
"H", "A", "B" A, B, H
none
"O"
IO IO
"H" H
anti-A, anti-B

 

Chart Of A-B-O Blood Donor & Recipient Compatibility

 

RECIPIENT
D
O
N
O
R
Alleles &
Antibodies
  O
anti-A
anti-B
  A
anti-B
  B
anti-A
  AB
None
O
None
None
None
None
A
Clump
None
Clump
None
B
Clump
Clump
None
None
AB
Clump
Clump
Clump
None

 

 

Note that blood-types A and B can be considered to be "codominant", as the presence of both alleles AB gives rise to a completely different phenotype, when compared to a homozgous AA or a BB equivalent.

 

What about Rhesus factors?.......these are a whole new set of antigens, discovered when blood from rhesus monkeys was injected into guinea pigas (circa 1940's).  There are over 50 different types of Rh factors, but the most comomonly known one is the D antigen (Rho[D]), which -if it is present- indicates that that person is Rh-positive; if the D antigen is absent, that person is Rh-negative

In contrast to the ABO system, however, antibodies to Rh antigens aren't necesssarily inherent to the person's blood, and can develop as an immune response after a blood transfusion, or during pregnancy.

At a mother's first antenatal screening, blood tests are taken in order to determine her blood type (A, B, AB or O) as well as her rhesus status (Rh-positive or Rh-negative).

If the mother has the rhesus factor (which is a protein on the surface of her red blood cells) then she is said to be Rh-positive. If not, then she is Rh-negative. 85% of people are Rh-positive.

The rhesus state only really begins to play a role during pregnancy if the mother is Rh-negative, the father is Rh-positive and the baby is also Rh-positive.

Rh(D) positive cells contain the D antigen, which can stimulate Rh(d) negative blood to produce harmful antibodies that can destroy red cells. The harmful antibody is called ‘anti-D’ antibody, and can be produced by a mother who is Rh-negative carrying a baby who is Rh-positive.

Rhesus incompatibility doesn’t cause any problems with a first pregnancy because (unlike the AB antibodies) the rhesus antibodies aren’t inherently present in the mother’s blood.

However, in subsequent pregnancies, if the babies are Rh-positive, there may be a problem. The mother’s antibodies can / will cross over the placenta into the baby’s blood causing a reaction.

This causes problems with the baby’s haemoglobin levels (the iron-carrying element in the red blood cells) which could then fall, causing anaemia. Blood transfusion would then be necessary (see chart below) at birth and the babies could also be severely jaundiced.

Gene Interactions
Some genes give rise to gene products that alter the effects (phenotypes) of other genes.

Epistasis

"the interaction of genes that are not alleles, in particular the suppression of the effect of one such gene by another."

Given that genes of any organism do not operate in total isolation from one another, but obviously are functioning in a common cellular environment. a phenomenon that occurs when the alleles of one gene covers up (or alters) the expression of alleles of another gene.

epistasis   epistasis

Labrador coat colour is an example of Epistasis in that there are two genes which affect coat colour -the "E" gene, which affects the presence of a dark pigment in the coat and the "B" gene, which governs the degree to which that pigment is present in the coat, where B_ gives rise to a "black lab", but only if the genotypes at the E locus are E_ or EE.

While blood groups would also be a more than adequate example of this phenomenon, a quite overt example of epistatic effect, albeit more indirect, would be life and death consequences!

In this instance the same gene that affects coat colour in the mouse also has some influence upon development of the embryo. Thus, one gene, does not always mean one function.   If, as in this case, It has more than one function and is therefore considerred to be pleiotropic.

Some might even argue that this is not technically "true" epistasis... Why? what do you think?

 

Ratios are important characteristics: 3:1 (and 1:1 -test cross) for monihybrid crosses and 9:3:3:1 for dihybrid crosses.

Extension of Mendelian Genetics:-

 

Another example is coat colour in mice in the example shown in the picture:

The B allele determines a banded pattern, called agouti.
The recessive b allele results in unbanded hairs.
The genotypes BB or Bb are, therefore, agouti.

The genotype bb is coloured solidly black .

Another gene, at an entirely different locus, determines if any coloration occurs at all.

The genotypes AA and Aa have color, whereas the double recessive aa are albino, which do not allow any colour to show through as the aa genotype blocks all pigment production.

Mice that are heterozygous for both genes are agouti.


An F2 phenotypic ratio of an initial parental cross between a BB, AA and a bb, aa would be: 9 agouti: 3 black: 4 white.

The corresponding genotypes are 9 agouti (1 BBAA + 2 BbAA + 4 BbAa):3 black (1 bbAA + 2 bbAa):4 albino (1 BBaa + 2 Bbaa + 1 bbaa).

Other examples of gene/allelic expression which differ from expected patterns of Medelian inheritance are:

 

Duplicate genes, occur when two distinct genes affect the same phentype in the same way.

One of the best examples of this would be the shape of the shepherd's purse pollen sac.

  

 

Complementary gene activity, occurs when two distinct genes affect the same phenotype in a complementary way, whereby the presence of BOTH dominant alleles are required to give a particular phenotype that is distinct from either being present by itself.

 

Polygenes also mediate quantitative inheritance.
Individual heritable characters are often found to be controlled by groups of several genes, called polygenes.

Each allele intensifies or diminishes the phenotype.
Variation is continuous or quantitative (“summation" or "adding up” of all the traits).
Examples of continuous characters are height, skin color, and (possibly) intelligence.

Incomplete dominance: eg. Four o' clocks, carnations. BLENDING 1 : 2 : 1
Codominance: eg. M and N blood groups on chromosome 4 having specific antigens M and N

1 : 2 : 1 but where the heterozygotes (MN) gives rise to a distinct phenotype

Multiple alleles ABO blood types, A and B are dominant to O , but A and B codominant to each other
Epistasis essentially "eliminates" or "masks" phenotypic expression of other genes,

eg. Labrador dogs fur colour, albinoism in mice

Lethal alleles eg. Yellow colouration in mice fur. 2 : 1 . Pleiotropy(?)
Several genes / same character Coat colour in mammals,

eg. mice

A (agouti), B (black/brown), C, (colour) D (intensity), S. (distribution) genes

Complementary gene activity eg. Pea plants, purple colouration. 9 : 7
Duplicate gene activity eg. Shepherd's purse, Round over narrow fruits, where

both A 1 - and A 2 - can cause heart shape 15 : 1

 

Nature vs. Nurture?
When thinking about the importance of either genotypes or phenotypes, one must always consider the immense importance of.....the environment , and how it can affect the action(s) of any given gene.

Variables such as light, temperature, and nutrition can dramatically affect the translation of a genotype into a phenotype.

For example, the darkness of the fur on extremities of a Siamese cat is affected by the temperature of that region. Darkened extremities normally have a lower temperature than the rest of the body.

Such colouration can be manipulated experimentally.

Bunnies

 

 

 

 

 

 


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