Molecular and General Genetics – BIOLOGY 261, Lecture Notes

Lectures 1 and 2.

Mendelian Genetic Analysis – Chapter 2

1. MENDEL’s FIRST LAW – Independent assortment.

Mendel’s first law applies to a genetic cross to monitor the segregation of a single gene with two
alleles.

Diploid organisms carry two copies of each gene. The genes can have variants, each variant is called
an allele – (for example, the blue and brown alleles of the human eye color gene). If we consider one
gene, a heterozygotic individual carries two different variants of the gene. When they produce
gametes (egg, sperm or pollen), each gamete has a 50/50 chance of receiving a particular allele of the
gene. For example, person who is heterozygous for the blue/brown eye color alleles will produce
gametes, each of which has a 50% chance of carrying a brown-eyed allele. During fertilization, two
gametes combine at random and the fertilized egg will again have two copies of the gene. The fusion
of the two gametes is random relative to the alleles that they carry. All possible pairwise combinations
of the alleles from each parent from the cross of two heterozygotes have an equal chance of occurring.

The key concept is that crosses or mating between parents with known genotypes produces offspring
with different genotypes and phenotypes at predictable frequencies or ratios. Genotype describes the
alleles that an individual carry; phenotype is what the appearance of the individual is. This may
include physical appearance or characterization at the biochemical level or DNA sequence level.

Female Gametes
Male A a
Gametes
A AA Aa
1.1. A cross between two heterozygotes:
Aa x Aa ® AA, Aa, aa 1:2:1 genotypic ratio
3:1 phenotypic ratio.
a Aa aa
1.2. A cross between a heterozygote and a heterozygote.
Aa x aa ® Aa, aa 1:1 genotypic ratio
1:1 phenotypic ratio.

If we know the genotypes of the parents, we can predict the genotypic and phenotypic ratios of
the offspring.
If we know the phenotypic ratio of the offspring, we can often decipher the genotypes of the
parents.
The class will need to be able to solve problems that carry out such deciphering.

2. TEST CROSS is a cross of a homozygous recessive individual (aa) to any other individual. It is
very informative for deciphering the genotype of the other individual. Any allele present in the “non-
tester” parent will be expressed in the offspring.

Aa x aa ® 1:1 Aa : aa
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3. PROBABILITY RULES

The product rule. The probability of two independent events occurring is the product of the two
individual probabilities. For example, in the cross described in (1) above, Aa x Aa, the probability of
having an individual receiving a recessive allele from its maternal parent is ½ and the probability of
receiving a recessive allele from its paternal parent is ½ ; the probability of both these events
happening is 1/2 x 1/2 = 1/4 .

The sum rule. The probability of having of having one or the other of two mutually exclusive events
is the sum of their individual probabilities. Consider again the cross described in (1) above, Aa x AA,

The probability an individual receiving a dominant allele from his maternal parent and recessive allele
from its paternal parent is ½ x ½ = ¼ .
The probability of the opposite happening, a recessive allele from its mother and a dominant allele
from its father is ½ x ½ = ¼.
The probability of the first case or the second case occurring is ¼ + ¼ = ½.

PROBABILITY AND RATIOS: "Expected segregation ratios", like 3:1, can be recognized in
large populations. However, even in small families, you can think of expected ratios in terms as
probabilities.
Example: If two individuals of "Bb" genotype mate and have one offspring there is a ¼ chance, (i.e
25%) that the offspring will be "bb" genotype. The frequency of a bb genotype will be 25%.

3. THE PEDIGREE

For species that don't produce very large numbers of offspring from a single mating pair (such as
humans), familial relationships and inheritance of traits are often represented by pedigree diagram.

By analyzing pedigree, we can often decipher the genetic control of a trait. The squares represent
males; the circles represent females. The rows represent generations, in this example parents with a
male and female offspring are represented.

The key elements of the pedigree to observe are:

1) An affected offspring resulting from the mating of two unaffected individuals indicates that this
trait is caused by a recessive allele. This also indicates that the parents were both heterozygotes.

2) It is a strong indication, though not proof, that the trait is controlled by a dominant allele if all
affected individuals in a pedigree have at least one affected parent.
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3) A high frequency of individuals being affected by a rare trait within a single family also suggests
the effect of a dominant allele.

In pedigree analysis, we often ask two questions: Is a trait controlled by a dominant or recessive
allele? What is the probability of a certain individual being affected by a certain genetic trait?

4. THE SIMPLE LOGIC OF GENETICS

1) If we know that a trait is controlled by different of alleles of a single gene or two genes we can
predict the inheritance of the trait based on probability.

2) The inverse is also true. If we can recognize a pattern of inheritance for a trait that is like a
Mendelian ratio 3:1 or 1:1, we can conclude that the trait is controlled by a single gene with two
alleles.
For example, we know that cystic fibrosis is caused by a single gene with at least one allele
that causes the disease. This is known because in families that have one affected child, 1 out of the 4
of the other children will also be affected – when averaged over a reasonably large number of families,
eg. 50 children total.
Huntington’s disease is also controlled by single gene, and the disease causing allele is
dominant. This became apparent when scientists realized that half of the children of a person with
Huntington’s disease were also affected by the disease.

5. MINI SUMMARY: WHAT ARE GENES AT THE MOLECULAR LEVEL – This summary
is to help you understand genes, but will be covered in detail in the second half of the course, after
the midterm.

The molecular basis of inheritance.

The body is made up of cells; each cell has a nucleus that contains chromosomes. The genes are on
the chromosomes. They are composed of DNA.

DNA is the template for RNA synthesis. RNA is translated into proteins. Proteins run the mechanics
of the cell.

DNA RNA Proteins Development and Metabolism

Mutations are changes in DNA sequence that create different alleles of a gene. These often leads to
non-functional proteins. The altered metabolism that results from mutations gives the varied
phenotypes that we see. Mutations in genes that encode the enzymes that synthesize pigments lead
to different colors found among individuals of a species. Altered proteins are the causes of many
human genetic diseases.

6. CHROMOSOMAL BASIS OF INHERITANCE

Mendel’s the laws of genetic inheritance were developed before we knew that genes are located on
chromosomes. Now we understand that the nature of the segregation of alleles and random nature of
fertilization that Mendel observed is based on the behavior of chromosomes during meiosis, the cell
division that gives rises to gametes.
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In diploid organisms, each cell has two sets of homologous chromosomes. Humans have 46
chromosomes, including 22 pairs of autosomal chromosomes and two sex chromosomes, the X or Y
chromosomes. The fruit fly, Drosophila melanogaster has 8 chromosomes, 3 pairs of autosomes and
2 sex chromosomes. The chromosomes are in pairs, and the pairs are nearly identical copies of each
other. The differences are primarily small changes in DNA sequence that lead to the different alleles
for genes.

Today we know that the segregation pattern of chromosomes during meiosis is the basis of gene
segregation. This was first hypothesized when scientists observed chromosomes under a microscope
and recognized that chromosome segregation resembled gene segregation described by Mendel.

Important vocabulary related to chromosomes:

Chromosome Centromere
Chromatid Sister Chromatids
Chromosome arm Homologous chromosomes,
also called homologous pairs of chromosomes.

Cell division
There are two types of cell division:

6.1 Mitosis - cell division that occurs in somatic cells (all cells except those producing gametes). In
mitosis, chromosomes replicate then divide in conjunction with cell division. This conserves the
number of chromosomes during cell division.

6.2. Meiosis - a particular kind of cell division in reproductive cells which give rise to gametes, i.e.
egg cells, sperm and pollen.
In meiosis, chromosome replication is followed by two cell divisions. The number of chromosomes
in a gamete is half of the number of chromosomes in a somatic cell because of meiosis. The first cell
division separates the members of each chromosome pair from each other; the individual
chromosomes maintain their duplicated structures during this first division (meiosis I). The second
division (meiosis II) splits each of the duplicated chromosomes into two daughter chromosomes.
The pairing of homologous chromosomes and their segregation into separate gametes accounts for
the segregation of alleles of a gene during gametogenesis. The random assortment of genes on
different chromosomes accounts for random assortment of genes.

6.3. How did early geneticists demonstrate that chromosomes carried the genetic material?

a. Chromosomes were found to determine sex type.

b. Gene inheritance correlated with sex chromosomal inheritance for some traits. These traits are
called sex linked traits.
c. Abnormal sex-linked gene inheritance occurred with abnormal sex chromosome inheritance.

7. SEX CHROMOSOMES

XX, XY - in humans, and flies. Individuals with two X chromosomes are female; males have an X
and a Y chromosome. The X and Y chromosomes pair during meiosis and males produce X and Y
gametes in equal numbers. Females produce gametes only with X chromosomes. Fertilization gives
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rise to XX and XY offspring.

ZZ, ZW - In birds the females have heteromorphic sex chromosomes, called Z and W.
Males have homomorphic sex chromosomes called ZZ. [“Hetero” means “different”,
“morphic” means “form”]

7.1. Sex linkage.

Disproportionate inheritance of a trait between male and female offspring usually indicates that a trait
is sex linked i.e. is a trait controlled by a gene on either the X or Y chromosome. (Most often, it is on
the X chromosome).

7.2. Genes on the X chromosome are passed from fathers to daughters and from mothers to either
daughters or sons.
Because males have only one X chromosome, there are some striking features of sex linkage
that are apparent when the X chromosome caries deleterious mutations such as hemophilia. Mothers
who are heterozygous carriers of deleterious recessive traits pass it to half her sons, and those sons all
manifest the trait. For rare recessive traits, daughters usually do not show the trait but half will be
heterozygous carriers of the deleterious.

Notes on gene symbols for recessive and dominant alleles, mutant and wild type vary, by
tradition and standardization for different species.

1. A, a In generic discussions when we may not know the system used for a particular
species the dominant allele is designated by capital letter and the recessive allele by a lower case
letter.

2. Drosophila: w, w+ B, B+ w,+ B,+

In Drosophila, a different system is used: The name of gene is based on the mutant type as
compared to the wild type fly. Lowercase letters are used if the mutant allele is recessive; capital
letters are used for dominant mutant alleles (w, - white eye, B - black body ) a plus superscript
indicates the wild type allele. Eg., w and B+ are recessive alleles, w+ and B are dominant alleles.

3. cf9, Cf9 . For many organisms, three letter symbols are preferred. In some species the first letter
is capitalized, in other species all three letters are capitalized.

4. E. coli, bacteria. In this course, we will use superscripts +/- to designate the normal and mutant
alleles e.g.: dcm+ or dcm-. However, when bacterial geneticists write a strain description they
only write the mutations and leave out superscripts. E.g., a strain that was written: dcm, met, would
be dcm- met- , that is mutant or inactive dcm or met genes.