Human Genetics

Single gene defects

Chromosomal disorders
Multifactorial (quantitative) traits

Single Gene Disorders

A single gene disorder is one that is
determined by a
________________________ and the
specific allele on one or both members of
a chromosome pair.
Single gene defects are rare, with a
frequency of less than ______________.

Single Gene Disorders

There are five basic patterns of single
gene inheritance:
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Maternal (mitochondrial) inheritance

Autosomal Dominant
Huntington syndrome
Progeria
Polydactyly

Trait

Chromosome for
Gene Location

Dominant
Phenotype

Possible
Dominant
Genotypes

Recessive
Phenotype

Recessive
Genotype

color of iris

not blue

EE or Ee

blue

ee

widow's
peak

peak

PP or Pp

no peak

pp

cheek
dimples

dimples

DD or Dd

not dimples

dd

face
freckles

freckles

FF or Ff

no freckles

ff

mid-digital
hair

10

hair

HH or Hh

no hair

hh

Hitchhiker
s thumb

17

straight

TT or Tt

curved

tt

Hallux
length
(toes)

20

long 2nd toe

BB or Bb

long big toe or =

to 2nd toe

bb

Ear lobes

21

free

LL or Ll

attached

ll

Tongue
rolling

22

ability

RR or Rr

no ability

rr

16

cleft

YY or Yy

no cleft

yy

Cleft chin

Tongue Rolling
A simple two-allele character, with the allele
for rolling (usually given the symbol T or R)
_______________________ over the allele
for non-rolling (t or r).

Cleft Chin
Separate cheek and chin dimple genes
Dimples on chromosome 5 and cleft chin on
chromosome 16
Cleft chin a classic example of
__________________
The appearance of a feature like a cleft chin is
dependent on two genes, the
__________________ and the cleft gene itself.
There is a ____________________ gene (M)
that when dominant, doesnt allow the cleft chin
gene to work

Dominant Lethal Genes

Spontaneous dominant mutation
normal height aa
Dwarfs Aa
AA lethal
affects less than 200,000 people in the US
population

Achondroplasia
Autosomal dominant mutation
Gene on chromosome 4 (4p16.3)
FGFR3 gene- fibroblast growth factor
receptor gene
____________________________
Severely shortened bones

Achondroplasia

3 out of 4 cases new mutation, spontaneous

Increase with age (>35 years old)
Exclusively inherited ____________________
99% cases two mutations of FGFR3
G1138A glycine to arginine in protein 98%
G1138C 1%

Missence mutation Lys650Met in tyrosinase

kinase severe achondroplasia with
developmental delay

Progeria
Hutchinson-Gilford Progeria Syndrome is an
extremely rare genetic disease that accelerates
the aging process to about seven times the
normal rate.
Because of this accelerated aging, a child of ten
years will have similar respiratory,
cardiovascular, and arthritic conditions that a 70year-old would have.
Progeria affects between
_________________________ (estimated
actual) and 1 in 8 million (reported) children,

Huntington Disease
Chromosome 4
Mutation of the gene causes Huntington
chorea, _________________________,
lethal in later age (1:10,000)
Deletion of the gene Wolf-Hirschhorn
syndrome, carriers die young

Huntington Disease
Gene contain CAG repeat (CAG) n - took
12 years to determine
n<35, you are fine
Usually 10-15 repeats
n>39 Huntington chorea, slow
deterioration of the intellect, muscular
activity, etc. Can last 15-25 years.

Huntington Disease
Gene codes for protein huntingtin
Another protein, HAP1, important for normal
functioning of hypothalamus, by linking to
transport proteins, protecting them and ensuring
normal growth of neurites
HAP1 needs to be phosphorylated to be active
Abnormal, or mutant huntingtin prevent
phosporylation of HAP1
http://www.yourgenesyourhealth.org/

Autosomal Recessive

Trait

Chromosome for Gene Location

Genotype
(normal)

skin cancer

Cc

cystic fibrosis

Qq

albinism

11

Aa

xeroderma pigmentosa

15

Xx

lung cancer

Nn

PKU (phenylketonuria)

12

Gg

Muscular Dystrophy

X sex chromosome

Mm (girls only)

Albinism
1:33,000 Caucasians
1:28,000 African American in US
Affects a gene for
______________________, an enzyme
used in conversion of tyrosine to DOPA,
from which the brown pigment melanin
derives
There are at least ______________ of
albinism

Albinism
Two main types:
Type 1
____________________________________,
autosomal gene(s), oculocutaneous (OCA);
white or pink skin, hair, iris color, vision
problems
Type 2 (OA) ocular albinism, affects only
_________________, no melanin in retina,
OA1 genetic defect in GPR143 gene,
chromosome X

Albinism
OCA genetic defect of tyrosinase enzyme in
converting tyrosinase to melanin:

OCA1A _______________________________
OCA1B tyrosinase is minimally active, some color
OCA3 genetic defect in TYRP1
OCA4 genetic defect in SLC45 protein
Combination of eight genes Hermansky-Pudlak
syndrome albinism, bleeding problems, bruising,
lungs, bowel diseases

Albinism
Any forms of albinism have some of the
following possible symptoms:
Rapid eye movements (nystagmus)
Strabismus (eyes not tracking properly)
Photophobia (avoidance of light because of
discomfort)
Decreased visual acuity or even functional
blindness

The TYRP1 gene is located on the short (p) arm of chromosome 9

at position 23.More precisely, the TYRP1 gene is located from
base pair 12,683,448 to base pair 12,700,257 on chromosome 9.

The GPR143 gene is located on the short (p) arm of

the X chromosome at position 22.3. More precisely, the GPR143
gene is located from base pair 9,653,453 to base pair 9,693,916
on the X chromosome.

OMIM http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300500

Eye color
In humans ______________________
involved in eye color are known.
They explain typical patterns of
inheritance of brown, green, and blue eye
colors.
Grey eye color, Hazel eye color, and
multiple shades of blue, brown, green, and
grey are not explained.

Eye Color
The known Human Eye color genes are:
EYCL1 (also called gey), the
_______________________________, located on chromosome
19 (though there is also evidence that another gene with similar
activity exists but is not on chromosome 19).
EYCL2 (also called bey1), the central brown eye color gene,
possibly located on chromosome 15.
EYCL3 (also called bey2), the _______________________ eye
color gene located on chromosome 15.

EYCL3 probably involves mutations in the regulatory

region just before the OCA2 gene (which produces a
protein that is expressed in melanocytes).
A second gene for green has also been postulated.
Other eye colors including grey and hazel are not yet
explained.

Eye Color Two Genes Model

For gene 1 (bey), there are two possibilities,
brown or blue. The brown is
___________________ over the blue one.
____________________________________
For gene 2 (gey), there are two possibilities,
green or blue. Green is
_________________________ blue and so G
usually represents green and b, blue.
______________________________________.
Brown is dominant over greenif you have a B
version of gene 1 and a G version of gene 2, you
will have brown eyes.

Epidermylosis bullosa
A genetic disease that affects 1:10,000 children
Lack of collagen type VII that anchors skin and
lining of gastrointestinal system to the body
The skin is fragile, tearing and blistering occur
with minimal friction
Solid food produces erosions of the esopahgus
Circulation stem cells from umbilical cord were
used for treatment

Metabolic Disorders
Disorders of carbohydrate metabolism,
amino acid metabolism, organic acid
metabolism, or lysosomal storage
diseases

Alkaptonuria
Alkaptonuria (black urine disease) sweat, urine
of brown color
a rare inherited genetic disorder of
______________________. This is an autosomal
recessive condition that is due to a defect in the
enzyme homogentisate 1,2-dioxygenase which
participates in the degradation of tyrosine.

A toxic tyrosine byproduct called homogentisic

acid (or alkapton) accumulates in the blood, and
is excreted in urine in large amounts. Excessive
homogentisic acid causes damage to cartilage
(leading to osteoarthritis) and heart valves as
well as precipitating as kidney stones.

Phenylketonuria (PKU)
One of the first disorders for which
biochemical basis was revealed
Phenylketonuria (PKU) is a genetic disorder
in which the body can't process amino acid
phenylalanine (Phe) essential aa.

Phenylketonuria (PKU)
Occurs in about 1 in 12,000 Caucasian births
Caused by a recessive mutation of a gene on
chromosome 12 (an autosome) at position
12q24
Gene codes for an enzyme phenylalanine
hydroxylase, which converts Phe into tyrosine
Tyrosine is needed for protein synthesis,
production of hormones thyroxine and
andrenaline, production of melanin
Has ______________________ effect

Lysosome Storage Diseases

Niemann-Pick syndrome
Affects breakdown and use of fats and
cholosterol
Causes harmful amount of lipids to acumulate
in the spleen, liver, lungs, bone marrow
Patients die before 10 years old
500 known cases worldwide

X-linked Inheritance
X-linked dominant
X-linked recessive

X-linked Dominant Inheritance

Example: vitamin D resistant rickets insufficient indigestion of vitamin D,

bone deformities

X-linked recessive Traits

Hemophilia, color blindness

Change In The Chromosomal

Number
Autosomal or sex chromosomes

Down Syndrome
______________________ chromosome
chr21 and/or translocation of chr14
Similar phenotype
Mental retardation
Absence of tumors

Turner Syndrome
Affected individuals with Turner's
syndrome (TS) are genetically 45, X
TS females have several distinguishing
characteristics such as
_________________________________
__ short stature, webbed skin behind the
neck, low hairline, widely spaced nipples,
small breast development, brown spots,
small finger nails, and ovarian failure

Kleinfelters Syndrome
Affected individuals with Klinefelter syndrome are
genetically 47, XXY
Paternal non-disjunction in meiosis I accounts for 53% of
cases, and maternal non-disjunction in meiosis I
accounts for 34% of cases.
distinguishing characteristics such as
_______________, tall stature, long arms and legs,
lanky build, feminized physique, low testosteron levels

Imprinting

The expression of some traits may depend upon which parent

contributes the alleles for those traits.
Two genetic disorders, Prader-Willi syndrome and Angelman
syndrome, are caused by the same deletion on chromosome 15.
The symptoms differ depending upon whether the gene was
inherited from the mother or from the father.
Prader-Willi syndrome is caused by a deletion from the paternal
version of chromosome 15. The syndrome is characterized by
mental retardation, obesity, short stature, and unusually small hands
and feet. (FROM THE FATHER)
Angelman syndrome is caused by a deletion from the maternal
version of chromosome 15. This syndrome is characterized by
uncontrollable spontaneous laughter, jerky movements, and other
motor and mental symptoms. (FROM THE MOTHER)

 Tests are available to determine in utero if a

child has a particular disorder.
One technique, amniocentesis, can be
used beginning at the 14th to 16th week of
pregnancy to assess the presence of a
specific disease.
Fetal cells extracted from amniotic fluid are
cultured and karyotyped to identify some
disorders.
Other disorders can be identified from
chemicals in the amniotic fluids.

 A second technique, chorionic villus

sampling (CVS) can allow faster
karyotyping and can be performed as early
as the eighth to tenth week of pregnancy.
This technique extracts a sample of fetal tissue
from the chrionic villi of the placenta.
This technique is not suitable for tests requiring
amniotic fluid.

Haplotype

The DNA sequence of any two people is 99.9 percent identical. The
variations, however, may greatly affect an individual's disease risk.
Sites in the DNA sequence where individuals differ at a single DNA
base are called single nucleotide polymorphisms (SNPs).
Sets of nearby SNPs on the same chromosome are inherited in
blocks.
This pattern of SNPs on a block is a haplotype.
Blocks may contain a large number of SNPs, but a few SNPs are
enough to uniquely identify the haplotypes in a block.
The HapMap is a map of these haplotype blocks and the specific
SNPs that identify the haplotypes are called tag SNPs.

http://www.genome.gov/page.cfm?
pageID=10001688

Getting Up Close and

Personal With Your Genome
A new type of company is offering
to scan a persons genome

Genome Analysis
Last month, the United States Senate
unanimously passed a measure expected
to encourage Americans to take
advantage of genetic testing.
When signed into law, the Genetic
Information Nondiscrimination Act (GINA)
will protect individuals against health
insurance and employment discrimination
based on their genetic information.

SNPs
23andMe and other similar companies
including deCODEMe (an offshoot of deCODE
Pharmaceuticals in Iceland, founded by
geneticist Kari Stefansson) and California-based
Navigenicsdetermine the pattern of hundreds
of thousands of single-nucleotide
polymorphisms (SNPs) across a persons
genome.
Because many SNPs are associated with
disease-causing forms of genes, having one
SNP versus another signals a higher
predisposition for developing certain conditions.

Genome Scans
For 2.5 ml of saliva and US$999, 23andMe, a
genetics startup company with headquarters in
California, delivers genetic information on 60 or
so conditionsfrom type II diabetes to earwax
type.
You can also find out about your maternal and
paternal ancestry and whether they share
common ancestors with Ben Franklin or U2s
frontman Bono.
It analyzes about 600, 000 SNPs