Principles of Genetics-Internal Medicine-2

nd
year-1
st

semester
Terms
Genes units of genetic information
Karyotype characteristic chromosome complement
of each species in terms of number and the
morphology of the chromosome that make up its
genome.
Locus precise position of each gene
Gene map the map of the chromosomal location of
the genes and is characteristic of each species and the
individual within a species.
Cytogenetics the study of chromosomes, and their
inheritance
satellite DNAs
microRNA (miRNA)
Transcription factors
Exons
Introns
Human Genome Project an international effort to
determine the complete content of the human
genome.
Genomic medicine seeks to apply a large scale
analysis of the human genome, including the control of
gene expression, human gene variation, and
interactions between genes and the environment, to
improve medical care.
Impact of Genetics on Medical Practice
Enhance understanding of disease etiology and
pathogenesis.
Plays important role in the:
Diagnosis
Prevention
Treatment of diseases
Classification of Genetic Disorders
Chromosome disorders
Single-gene defects
Multifactorial inheritance


Human Genome
The sum total of the genetic information of the human
species.
Consists of large amounts of DNA that contains within
its structure the genetic information needed to specify
all aspects of
Embryogenesis
Development
Growth
Metabolism and
Reproduction
Human Genome
Consist of 46 chromosomes arranged in 23 pairs 22 are alike in
males and females autosomes. The remaining pair sex
chromosomes XX female XY male
Cloning of Genes
Cloning refers to the creation of a recombinant DNA
that can be propagated indefinitely.
recombinant DNA DNA deliberately coupled from
different sources
Libraries refers to a collection of DNA clones
Genomic library
cDNA libraries
Nucleic Acid Hybridization
Southern blot
Northern Blot
Microarray technology DNA microarray chips
Mutation
Any change in the primary nucleotide sequence of DNA
regardless of its functional consequences.
Can occur in the germline (sperm or
oocytes) or
During embryogenesis or in somatic tissues
Can involve the entire genome or affect the number of
chromosomes in the cell or alter individual genes
Much greater in the male germline than the female
germline
May or may not have phenotypic effect
Categories of Human Mutations
Genome mutation mutations that affect the number
of chromosomes in the cell
Alterations in the number of intact
chromosomes (aneuploidy) arising from
errors in chromosome segregation during
meiosis or mitosis.
A genome mutation that deletes or
duplicates an entire chromosome alters the
dosage and thus expression levels of
hundreds or thousands of genes.
Chromosome mutations are mutations that alter the
structure of individual chromosomes
Changes involve only a part of a
chromosome
Can occur spontaneously or may result from
abnormal segregation of translocated
chromosomes duringmeiosis
A chromosome mutation that deletes or
duplicates large portions of one or more
chromosomes affect the expression of
hundreds of genes
Gene mutation mutations that alter individual genes.
Changes in DNA sequence of the nuclear or
mitochondrial genomes, ranging from a
change in a single nucleotide to changes in
millions of base pairs.
May lead to complete loss of expression of
the gene or to formation of a variant
protein.
Clinical Cytogenetics
The study of chromosomes, their structure and their
inheritance, as applied to the practice of medical
genetics
Chromosomal Identification
G Banding (Giemsa banding)
Q Banding (Quinacrine mustard banding)
R Banding
Clinical Indicators for Chromosomal Analysis
Problems of early growth and development
Stillbirth and neonatal death
Fertility problems
Family history
Neoplasia
Pregnancy in women of advanced age (pre-natal
diagnosis)
Chromosome Abnormalities
May be either
Numerical or
Structural
One or more autosomes, sex chromosomes,
or both simultaneously
Most common type
Aneuploidy an abnormal chromosome
number due to an extra or missing
chromosome, which is always with physical
or mental development or both.
Reciprocal translocation an exchange of
segments between non-homologous
chromosomes.
Phenotypic consequences depends on its
Specific nature
The resulting imbalance of involved parts of
the genome
The specific genes contained in or affected
by the abnormalitys
The likelihood of its transmission to next
generations
Numerical Abnormalities
Aneuploidy
The most common and clinically significant
type of human chromosome disorder
Occurs in at least 5% of all clinically
recognized pregnancies
Most have either trisomy (three instead of the normal pair of a
particular chromosome or, less often, monosomy (only one
representative of a particular chromosome).
Monosomies are more deleterious than trisomies.
Complete monosomies are generally not
viable except for monosomy X
Complete trisomies are viable for
chromosomes 13, 18, 21, X, and Y


Structural Abnormalities
Structural rearrangements results from chromosome
breakage, followed by reconstitution in an abnormal
combination.
Can be present in:
Balanced if the chromosome set has normal
complement of chromosomal material
Unbalanced if there is additional or missing
material
Some rearrangement are stable, capable of passing
through mitotic and meiotic cell divisions unaltered, or
unstable.
Variations in Gene - Terms
Locus a segment of DNA occupying a particular
position or location on a chromosome
Alleles alternative forms of a gene or a genetic
marker
Wild-type or Common allele the normal or common
allele
Variant or mutant differ from wild-type because of
presence of a mutation
Haplotype a given set of alleles at a locus or cluster
of loci on a chromosmoe
Polymorphism if there are at least two relatively
common alleles at the locus in the population.
Genotype and Phenotype
Genotype the genetic information defining the trait;
the set of alleles that make up a person genetic
constitution either collectively at all loci or at a single
locus
Phenotype an observed trait; the observable
expression of a genotype as a morphological,clinical,
cellular, or biochemical trait
Single-gene disorder
Homozygous (a homozygote) when alleles
at a given are identical
Heterozygous (a heterozygote or carrier)
if the alleles are different on the maternal
and the paternal copy
Compound heterozygote if two different
mutant alleles are inherited at a given locus
Hemizygous used to describe males with a
mutation in an X chromosomal gene or a
female with a loss of one X chromosome.
Pedigrees
Single-gene disorders are characterized by their
patterns of transmission in families.
To establish the pattern of transmission, the usual first
step is to obtain information about the family history
of the patient and summarize the details
Pedigree a graphical representation of the family
tree, with use of standard symbols.
Kindred the extended family depicted in a pedigree
Proband (propositus or index case) the member
through whom a family with a genetic disorder is first
brought to the attention.
Consultand - the person who brings the family to
attention
Sibs brothers and sisters
Relatives
1
st
degree parents, sibs, and offspring of
the proband)
2
nd
degree grandparents,uncles and aunts,
nephews and nieces, and half-sibs)
3
rd
degree first cousins
Consanguineous couples who have one or more
ancestors in common
Sporadic case if the disorder is determined to be due
to new mutation
Fitness a measure of the impact of a condition on
reproduction
Mendellian Inheritance
The pattern shown by single-gene disorders in
pedigree depend on chiefly on two factors:
Whether the phenotype is dominant
(expressed when only one chromosome of a
pair carries the mutant allele and the other
chromosome has a wild-type allele at that
locus) or recessive (expressed only when
both chromosomes of a pair carry mutant
alleles at a locus); and
The chromosomal location of the gene
locus, which may be on an autosome
(chromosome 1 to 22) or a sex chromosome
(chromosome X and Y)



Basic Patterns of Single-Gene Inheritance
Autosomal Recessive
Autosomal Dominant
X-linked Dominant
X-linked Recessive
Dominant and Recessive Inheritance
Recessive inheritance a phenotype expressed only in
homoxygous (or, for X-linked traits, male hemizygous)
and not in heterozygotes.
Most are due to mutations that reduce or
eliminate the function of the gene (loss-of-
function)
Dominant Inheritance a phenotype expressed in
both homozygotes and heterozygotes for a mutant
allele
Factors Affecting Pedigree Patterns
Penetrance is the probability that a gene will have
any phenotypic expression at all.
Reduced penetrance expression of
phenotype less than 100%
Expressivity the severity of expression of the
phenotype among individuals with the same disease-
causing phenotype
Variable expressivity when the severity of
disease differs in people who have the same
genotype



Stem Cells
Undifferentiated progenitors
o Totipotent- able to generate whole
organism (e.g. zygote).
o Pluripotent
o Multipotent
Endoderm
Mesoderm
Ectoderm

Most studied: hematopoietic stem cell
Telomeres-terminal positions of chromosomes
Hematopoietic Stem Cell
o Ability to express CD34