Chapter 24

Genetics and Genomics

  • Genetics: Study of the inheritance of characteristics

    Can help person prepare for inherited diseases and traits in offspring

  • Genes: DNA sequences that encode specific proteins

  • Genome: A complete set of genetic instructions in a person’s cells

  • Exome: Consists of the protein making genes of the genome; this accounts for
    <2% of the 3.2 billion DNA bases of the human genome

  • Chromosome 7 is one of the structures that organizes and stores DNA, and it contains important genes critical for normal bodily functions and health.

Cystic fibrosis: A genetic disorder that results in defective chloride ion channels
in cell membranes; results in thick mucus, which affects especially the lungs and pancreas

Karyotype

  • Chart displaying 23 chromosome pairs in size and order

  • Pairs 1 to 22 are autosomes, which determine traits, but not sex

  • Pair 23 is the sex chromosome (XX female, XY male); codes for sex

Alleles:

  • Various forms of a gene, which differ in DNA sequence

  • A person who has 2 identical alleles of a particular gene is

    homozygous for that gene. Example: AA or aa

  • A person with 2 different alleles for a gene is heterozygous. Example: Aa

Chromosomes and Genes are Paired

  • Genotype: Particular combination of alleles for a
    particular gene or genes. Letters

  • Phenotype: Appearance of a trait or health condition that
    develops as a result of the ways the genes are expressed physically.

    Example: thick mucous

    Types of alleles (often only exist in 2 types):

  • Dominant: Allele that masks expression of recessive
    allele, when there are present in a heterozygote

  • Recessive: Allele that may be masked by dominant
    gene, when present in a heterozygote



Punnett Square:
• Table used to predict probabilities of genotypes in offspring for certain traits
• father’s alleles are listed above, mother’s alleles are listed to left of boxes

Pedigree:
• Diagram showing family relationships, and known genotypes and phenotypes
for each family member
• Circles represent females, and squares represent males
• Shaded areas represent affected people, half-shaded areas are carriers,
unshaded are unaffected people

Mendelian Inheritance:
• Inheritance in which traits are regulated in dominant/recessive manner
• Phenotype of a heterozygote is determined by dominant allele

Example of Mendelian Inheritance: Albinism
•An autosomal recessive disorder, mode of inheritance that results in the absence of melanin production in the skin, hair, and eyes, leading to lighter pigmentation.

Homozygous dominant (AA) and heterozygous (Aa) genotypes have
normal melanin and skin pigmentation

Homozygous recessive (aa) genotype is albino—no melanin is
produced
• Possible genotypes for offspring of 2 heterozygous parents:
• AA: 25%
• Aa: 50%
• aa: 25%

Example of Mendelian Inheritance: Huntington’s Disease
• An autosomal dominant disorder, in which a child will have the
disorder if only 1 mutant allele is inherited
• Involves loss of coordination, uncontrollable dance-like movements,
behavioral changes, cognitive decline, beginning in 30s or 40s
• hd hd = healthy, unaffected
• HD hd = affected with Huntington disease


Example of Mendelian Inheritance: Cystic fibrosis
• An autosomal recessive disorder
• Abnormal chloride channels; thick, sticky mucus clogs lungs and
pancreas
• For 2 heterozygous parents, offspring can have 3 different genotypes:
• CF CF = homozygous dominant; healthy, noncarrier
• CF cf = heterozygous, unaffected, carrier
• cf cf = homozygous recessive; affected with CF
Mechanism of action example: defective chloride ion channels for cystic fibrosis

Mendelian extensions: Modes of inheritance which are not strictly controlled by
one gene with 2 versions of the allele
• Types of Mendelian extensions:
• Codominance - ABO blood type
• Incomplete dominance
• Multiple alleles - ABO blood type
• Pleiotropy
• Sex-linked inheritance


Codominance

  • What it means: Both alleles (gene versions) are fully expressed in a heterozygous individual.

  • Example in blood type:

    • The A allele and B allele are codominant.

    • If someone inherits an A allele from one parent and a B allele from the other, their blood type will be AB because both A and B are expressed equally.

    • ABO blood type is an example

Multiple Alleles

  • What it means: There are more than two possible versions (alleles) of a gene in the population.

  • Example in blood type:

    • The blood type gene has three possible alleles: A, B, and O.

      • A and B are dominant.

      • O is recessive (only shows up when no A or B is present).

Incomplete Dominance

  • Multiple levels/versions of a disease

  • Inheritance in which the phenotype of a heterozygote is intermediate between
    those of the homozygotes

Example: Sickle cell anemia
• Normal hemoglobin allele (S) does not completely mask recessive allele (s)
for abnormal hemoglobin and sickled red blood cells:
• SS genotype is normal, ss genotype has sickle cell anemia
• Heterozygous Ss genotype has sickle cell trait, mild form of sickle cell
anemia


Example: Familial hypercholesterolemia
• Increases blood cholesterol, raises risk of developing cardiovascular disease
• Homozygous dominant person has normal numbers of cholesterol receptors
on liver cells, and can remove cholesterol from blood
• Homozygous recessive person has no LDL receptors on liver cells; may
develop fat deposits around eyes or joints; develops disease in childhood
• Heterozygous person has ½ normal LDL receptors on liver cells; develops
disease in adulthood

Polygenic traits:

  • Traits that are influenced by multiple genes working together, rather than being determined by a single gene.

  • These traits often show a wide range of variation in a population because many genes contribute small effects to the final result.

Examples: height: skin color, eye color

Pleiotropy:
• A single gene contributes to several traits, or shows multiple effects
• People in the same family with the same genetic disorder may produce
several different symptoms
• Often seen in genetic diseases that affect a protein that is found in different
areas of the body


• Example: Marfan syndrome (an autosomal dominant defect)
• Defect in fibrillin, a protein found in elastic connective tissue in lens of eye, bones of
limbs and ribs, in aorta
• Possible symptoms: dislocation of lens of eye, long limbs, spindly fingers, caved-in
chest, weakness in wall of aorta
• Different people with Marfan syndrome may display different symptoms

Sex-linked Traits:
• Coded for by genes on a sex chromosome, mainly X chromosome
• Males carry only one X chromosome, so they exhibit recessive X-
linked traits more frequently than females

X-linked traits:
• Traits transmitted on X chromosome
• Males express X-linked trait with 1 copy of recessive gene; there are no male
carriers
• Females with 1 recessive gene for X-linked trait are normal carriers, and
require 2 recessive genes to express trait
• Examples: Red-green Colorblindness, Hemophilia, Duchenne muscular
dystrophy


Y-linked traits:
• Traits transmitted on Y chromosome
• Some genes are unique only to the Y chromosome, and are associated with
male characteristics

Reversed Sex Individual:
• If the SRY gene is expressed in an irregular manner, this can result in a
“reversed sex” person
• Person would have XY chromosomes and female genitalia


Crossing over of SRY gene of Y chromosome onto X chromosome:
• Crossing over occurs during meiosis
• Chromosomal XX female is a phenotypic male


Intersex conditions:
• Gene expression can also result in an incomplete sex reversal
• Person can have aspects of male and female anatomy
• Results from irregularities in the biochemical pathway that is started by
the SRY transcription factor

Genetic Determination of Intersex
5- Alpha Reductase Deficiency:
• 5-Alpha Reductase is the enzyme that converts testosterone to DHT
• Prevents formation of penis in XY person
• Identified as female at birth, but has male internal reproductive tract

Androgen Insensitivity Syndrome (AIS):
• A gene on the X chromosome codes for androgen receptors
• Mutation results in lack of androgen receptors, so developing structures
cannot respond to testosterone and DHT
• Prevents development of male internal and external reproductive structures
• XY person with AIS appears female

Gene expression can vary between individuals, even if they have the same genetic makeup (genotype). This variation is influenced by other genes and the environment. Two key terms explain these differences: penetrance and expressivity.

  1. Penetrance:

    • Refers to whether a person expresses a phenotype at all.

    • It is an all-or-none concept:

      • If penetrance is complete, everyone with the disease-causing alleles shows the trait.

      • If penetrance is incomplete, some people with the alleles don’t show the trait.

  2. Expressivity:

    • Refers to the degree or intensity of a phenotype.

    • People with the same genotype may show the trait to different extents.

Examples

  1. Polydactyly (extra fingers or toes):

    • Incomplete Penetrance:

      • Not everyone with the allele for polydactyly shows the trait (some have normal digits).

    • Variable Expressivity:

      • Among those who do show the trait, the number and placement of extra digits can vary widely (e.g., one extra finger vs. multiple extra toes).

Genetic Heterogeneity Explained

Genetic heterogeneity occurs when the same phenotype (observable trait or condition) can be caused by different genes. This happens when multiple genes are involved in a process, such as a biochemical pathway, and mutations in any one of these genes can disrupt the pathway, leading to the same outcome.

Example: Hereditary hearing impairment
• About 200 forms result from abnormalities in different genes
• Each gene affects different aspects of hearing


Example: Blood clotting disorders
• Several types of bleeding disorders exist
• Result from mutations in any of the genes that code for any of
the enzymes in the clotting pathways
• Mutations in different clotting enzymes will result in different
clotting times

Hormone effects on phenotype

Sex-limited trait:
• Affects a structure or function of the body that is present in only
males or only females
• Genes are either X-linked or autosomal
• Examples: beard growth or size of breasts


Sex-influenced inheritance:
• An allele is dominant in one sex and recessive in the other
• Genes are either X-linked or autosomal
• Based on hormonal differences between sexes
• Example: Baldness allele is dominant in males, recessive in females;
heterozygous males are bald, but heterozygous females are not

Multifactorial inheritance:

Traits affected by factors inside body or external
environment
• Examples: Eye color, height, and skin color
• Examples: Common diseases such as heart disease,
diabetes mellitus, hypertension, and cancers

Chromosome Disorders
• Changes from the normal chromosome number of 46
• Chromosomes can also rearrange, as in inversion of a
part of a chromosome, or exchange of parts between
nonhomologous chromosomes
• Rearrangements may interfere with a vital gene or result
in gametes with incorrect amount of genetic material

Aneuploidy

  • Euploid: Cells that have a normal number of chromosomes (2n = 46 chromosomes = diploid)

  • Aneuploid: Cells are missing a chromosome or having an
    extra one

  • Results from meiotic error called nondisjunction, that
    results in uneven separation and distribution of
    chromosomes

  • In nondisjunction, a chromosome pair fails to separate during meiosis, resulting in a sperm or egg with 2 or 0 copies of a chromosome instead of the normal 1 copy.

  • When an abnormal gamete fuses with a normal gamete at
    fertilization, the zygote has either 47 or 45 chromosomes instead of 46

Extreme Case of Aneuploidy: Polyploidy
• Most drastic upset in chromosome number
• Involves having an entire extra set (or sets) of chromosomes
• Results from formation of diploid, rather than normal haploid,
gamete
• If a diploid gamete participates in fertilization with a haploid
gamete, the zygote is triploid, having 3 copies of each
chromosome.
• Most triploid embryos or fetuses die, but occasionally an infant
survives a few days but has multiple abnormalities

Autosomal aneuploidy usually results in intellectual disability,
since so many genes contribute to brain function.
• Missing genetic material is more dangerous than extra material
• Trisomy: Having an extra chromosome; examples:


• Down Syndrome (Trisomy 21): Most common autosomal
aneuploid condition; less severe than Patau or Edward syndrome
• Patau syndrome (Trisomy 13): Usually results in miscarriage; if born,
baby has underdeveloped face, extra or fused fingers and toes, heart
problems, cleft lip or palate
• Edward syndrome (Trisomy 18): Usually results in miscarriage too; if
born, baby has similar problems as Trisomy 13, unusual finger position,
and extra flaps of skin in abdominal area
• Monosomy: Missing a chromosome

Aneuploidy
• Sex chromosome aneuploids:
• Less severely affected than autosomal aneuploids
• Turner’s syndrome, XO, often only delayed sexual development
and infertility, but some have low-set ears and extra skin on back of
neck
• Triplo-X, XXX, causes tall stature and menstrual irregularities, but
not many other symptoms
• Klinefelter’s syndrome, XXY, causes sexual underdevelopment,
breast growth, long arms and legs, enlarged hands and feet
• Jacob’s syndrome, XYY, causes tall stature, tremors, and problems
with language, coordination, muscle strength, behavior
• OY embryo does not survive, due to lack of genetic material from X
chromosome