TOPICS & REFERENCES

• Introduction to Genetics.
• Modern Genetic Terminology.
• Chromosomal Theory of Inheritance.
• Incomplete, or Partial, dominance.
• Codominance.
• Pleiotropy - Sickle-cell anemia;
Phenylketonuria (PKU); Marfan’s
syndrome.
• Penetrance.
• Expressivity - Neurofibromatosis
(NF1);
• Splithand deformity.
• Genomic (parental) Imprinting and
Gene silencing - Prader-willi and
Angelman syndromes.
• Mitochondrial inheritance.
• Pedigree Analysis.
 Introduction to Genetics.
The medical geneticist is usually a physician who works as part of a team of health care providers,
including many other physicians, nurses, and genetic counselors, to evaluate patients for possible
hereditary diseases.
 A pediatrician evaluates a child with multiple congenital malformations and orders a high-resolution
genomic test for submicroscopic chromosomal deletions or duplications that are below the level of
resolution of routine chromosome analysis
 An obstetrician sends a chorionic villus sample taken from a 38-year-old pregnant woman to a
cytogenetics laboratory for confirmation of abnormalities in the number or structure of the fetal
chromosomes, following a positive screening result from a noninvasive prenatal blood test
 A neurologist and genetic counselor provide APOE gene testing for Alzheimer disease susceptibility for a
woman with a strong family history of the disease so she can make appropriate long-term financial plans
 A gastroenterologist orders genome sequence analysis for a child with a multiyear history of life-
threatening and intractable inflammatory bowel disease. Sequencing reveals a mutation in a previously
unsuspected
Medical Genetics
• Categories of medical Genetic disease:

1. Chromosome disorders
2. Single-gene defects
3. Multifactorial disease with complex inheritance
Chromosome disorders

In chromosome disorders, the defect is due not to a

single mistake in the genetic blueprint but to an
excess
or a deficiency of the genes located on entire
chromosomes or chromosome segments. For
example, the presence
of an extra copy of one chromosome, chromosome
21, underlies a specific disorder, Down syndrome,
even
though no individual gene on that chromosome is
abnormal.
Single-gene defects

Single-gene defects are caused by pathogenic

mutations in individual genes. The mutation may
be present on both chromosomes of a pair (one of
paternal origin and one of maternal origin) or on
only one chromosome of a pair (matched with a
normal copy of that gene on the other copy of
that chromosome).

1. Cystic fibrosis
2. Sickle cell anemia
3. Marfan syndrome
 Multifactorial disease
 Multifactorial disease with complex inheritance describes the
majority of diseases in which there is a genetic contribution, as
evidenced by increased risk for disease (compared to the
general public) in identical twins or close relatives of affected
individuals, and yet the family history does not fit the
inheritance patterns seen typically in single-gene defects.

1. Hirschsprung disease
2. Cleft lip and palate
3. Congenital heart defects
Terminology
• Gene - A gene is the basic physical and functional unit of
heredity. Genes are made up of DNA. Some genes act as instructions to
make molecules called proteins. However, many genes do not code for
proteins. In humans, genes vary in size from a few hundred DNA bases
to more than 2 million bases.
• Chromosome - is a long DNA molecule with part or all of the
genetic material of an organism. Most eukaryotic chromosomes include
packaging proteins called histones which, aided by chaperone proteins,
bind to and condense the DNA molecule to maintain its integrity
• Chromatin - is a substance within a chromosome consisting of
DNA and protein. The DNA carries the cell's genetic instructions. The
major proteins in chromatin are histones, which help package the
DNA in a compact form that fits in the cell nucleus
• Chromatid is one of two identical halves of a replicated
chromosome. During cell division, the chromosomes first replicate so
that each daughter cell receives a complete set of chromosomes.
Modes of inheritance
 Incomplete Dominance

• Unlike the Mendelian crosses, a cross

between parents with contrasting traits
may sometimes generate offspring with
an intermediate phenotype.
• For example, if a four-o’clock or a
snapdragon plant with red flowers is
crossed with a white-flowered plant, the
offspring have pink flowers. Because
some red pigment is produced in the F1
intermediate-colored plant, neither the
red nor white flower color is dominant.
Such a situation is known as incomplete,
or partial, dominance.
 Tay-sachs disease
• Clear-cut cases of incomplete dominance are relatively rare. However, even when one allele seems to have complete
dominance over the other, careful examination of the gene product and its activity, rather than the phenotype, often
reveals an intermediate level of gene expression. An example is the human biochemical disorder Tay–Sachs disease, in
which homozygous recessive individuals are severely affected with a fatal lipid-storage disorder and neonates die
during their first one to three years of life. In afflicted individuals, there is almost no activity of hexosaminidase A, an
enzyme normally involved in lipid metabolism. Heterozygotes, with only a single copy of the mutant gene, are
phenotypically normal, but with only about 50 percent of the enzyme activity found in homozygous normal
individuals.
• Fortunately, this level of enzyme activity is adequate to achieve normal biochemical function. This situation is
notuncommon in enzyme disorders and illustrates the concept of the threshold effect, whereby normal phenotypic
expression occurs anytime a minimal level of gene product is attained. Most often, and in particular in Tay–Sachs
disease, the threshold is less than 50 percent.
 Codominance
If two alleles of a single gene are responsible for producing two distinct, detectable gene
products, a situation different from incomplete dominance or dominance/recessiveness
arises. In this case, the joint expression of both alleles in a heterozygote is called
codominance

• The information stored in any gene is extensive, and mutations can modify this information in many ways. Each
change produces a different allele. Therefore, for any gene, the number of alleles within members of a population need
not be restricted to two. When three or more alleles of the same gene—which we designate as multiple alleles—
are present in a population, the resulting mode of inheritance may be unique. It is important to realize that multiple
alleles can be studied only in populations. Any individual diploid organism has, at most, two homologous gene loci
that may be occupied by different alleles of the same gene. However, among members of a species, numerous
alternative forms of the same gene can exist.
 The ABO blood groups.
• The simplest case of multiple alleles occurs when three alternative alleles of one gene exist. This situation is
illustrated in the inheritance of the ABO blood groups in humans, discovered by Karl Landsteiner in the early 1900s.
The ABO system, like the MN blood types, is characterized by the presence of antigens on the surface of red blood
cells. The A and B antigens are distinct from the MN antigens and are under the control of a different gene, located
on chromosome 9. As in the MN system, one combination of alleles in the ABO system exhibits a codominant mode
of inheritance.
• The ABO phenotype of any individual is ascertained by mixing a blood sample with an antiserum containing type A
or type B antibodies. If an antigen is present on the surface of the person’s red blood cells, it will react with the
corresponding antibody and cause clumping, or agglutination, of the red blood cells. When an individual is tested in
this way, one of four phenotypes may be revealed. Each individual has the A antigen (A phenotype), the B antigen (B
phenotype), the A and B antigens (AB phenotype), or neither antigen (O phenotype).

 In these assignments, the IA and IB alleles are dominant to

the i allele, but codominant to each other.
Our knowledge of human blood types has several practical
applications, including compatible blood transfusions
and successful organ transplants.
 Pleiotropy - Sickle-cell anemia. Phenylketonuria (PKU)
Marfan’s syndrome
While the previous sections have focused on the effects of two or more
genes on a single characteristic, the converse situation, where expression of
a single gene has multiple phenotypic effects, is also quite common. This
phenomenon, which often becomes apparent when phenotypes are
examined carefully, is referred to as pleiotropy. Many excellent examples
can be drawn from human disorders, and we will review two such cases to
illustrate this point.
1.Marfan syndrome
2.Porphyria variegate
3.Phenylketonuria (PKU)
4.Sickle-cell anemia
 Penetrance and expressivity
The percentage of individuals that show at least some degree of expression of a mutant
genotype defines the Penetrance of the mutation.
Expressivity reflects the range of expression of the mutant genotype.
 Genomic (parental) imprinting and gene
silencing
• The term imprinting implies a type of marking process that has a memory.

• The term genomic imprinting refers to an analogous situation in which a

segment of DNA is marked, and that mark is retained and recognized
throughout the life of the organism inheriting the marked DNA.

• The Imprinting of Genes Is a Molecular Marking Process That Involves

DNA Methylation