Genetics of Human

Marie Černá

Lecture No 422-H

Human Genome Project

• Genome – the complete set of information in an organism’s DNA

• Human genome (1 haploid set) – 1 m long:30 000 genes – a gene ~ 30 000 bp long

(dystrophin gene 2 400 000 bp long)3 x 109 nucleotides (base pairs – bp, b)3 000 cM (centiMorgans - 1 cM = 1 Mb)chance of recombination between 2 loci

Human Genome Project

Basic genetic terms:

• GENE - a sequence of DNA molecule that determines primary structure of another macromolecule (polypeptide or non-translated RNA)

• GENOME – set of all genes in a cell or in an organism

• GENOTYPE – genetic constitution of a single locus or genetic constitution of all loci

• PLEIOTROPY – mutation of a single gene has multiple phenotypic effects - symptoms (syndrome = set of symptoms)

• MODIFICATION – nonheritable change of phenotype

• PHENOCOPY – nonheritable change of phenotype imitating certain genotype (peroxide blonde)

• LOCUS – the position on the chromosome =the allele localization

• ALLELE – particular (alternative) form of a gene

Allele• standard, allele polymorphism

= 2 and more standard allele per 1 gene• mutant, multiple allelia

= 2 and more mutant allele per 1 gene= allelic heterogeneity

• HETEROGENEITY - allelic – two and more alleles of one gene in population

lead to the same or similar phenotype(Duchenne and Becker muscular dystrophy)

- nonallelic (locus) – mutations of different genes lead to the same or similar phenotype (congenital deafness ) = GENOCOPY

Monogeny Polygeny Heterogeny Pleiotropy Gene linkage

Gene

mutation

or or

Trait

Example cystic fibrosis

height deafness phenylketonuria hemophilia daltonism

m.dystrophy

PHENOTYPE – observed biochemical, physiological and morphological characters determined by genotype and environment in which this genotype is expressedgenotype + environment

CHARACTERS : monogenic, qualitative

- superiority of genotype – 1 gene of big effect (major gene)

polygenic, quantitative, multifactorial - significant influence of the environment– more genes of small and additive effect (minor genes)

Monogenic inheritance Mendelian genetics – 10%

rare disease = occurrence ≤1:2000total 7 000 rare diseases400 mutations per man

• autosomal – independent on the sex,genes localized on autosomes

• gonosomal – dependent on the sex,genes localized on gonosomes X or Y

Monogenic inheritancebalanced polymorphismheterozygote advantage

• complete dominance:at the level of all organism

• incomplete dominance:at the biochemical level

• codominance (blood group):at the molecular level

Sickle cell disease (AR)

Sickle cell disease (AR)

Sickle cell disease (AR)

Sickle cell disease (AR)

Thalassemia alpha (AR)

Thalassemia alpha (AR)

Thalassemia beta (AR)

Thalassemia beta (AR)

Thalassemia beta (AR)

Glucose-6-phosphate dehydrogenase deficiency (XR)

Polygenic inheritance multifactorial – 90 %

many genesenvironmental effect

on phenotype

Gaussian distributionquantitative

character

Interaction of environment and genotype

• Internal environment: hormones– premature baldness– atherosclerosis

• External environment: nutrition, temperature

– quantity + quality of nutrition and height – termolabile enzyme

for dark pigment in rabbits

Interaction of environment and genotype

gene pool1 gene pool

2

gene pool3

gene pool4

gene pool5

external factor 1

external factor 2

external factor 3

external factor 4

external factor 5

Atherosclerosis

is a degenerative disease of the vessel wall.Clinically, it is manifested by serious and

frequent complications:• ischemic heart disease• cerebrovascular accident (stroke)• ischemic disease of lower limb

Risk factors of atherosclerosisunaffectable• personal history - ischemic heart disease or

another manifestation of atherosclerosis• genetic factors - family history of ischemic heart

disease or another manifestation of atherosclerosis: in relatives of the first degree, ♂ up to the age of 55 and ♀ up to the age of 65

• sex – higher risk in ♂ than in ♀ - hormones• age – higher risk in ♂ above 45 years of age and

in ♀ above 55 years of age

Risk factors of atherosclerosis

affectable• hyperlipoproteinemia (↑LDL and ↓HDL cholesterol)• smoking cigarettes• arterial hypertension• disorder of saccharide tolerance (diabetes mellitus)• obesity of central type• lack of physical activity• increased level of homocystein• increased level of uric acid (gout)• increased level of thrombogenic factors (fibrinogen)

Heritability of atherosclerosis

• in 80-90% of population is a tight balanced state between genetic and environmental factors (multifactorial)

• 5-10% of population has a considerable genetic predisposition (polygenic)

• 5-10% of population has a considerable genetic resistance (polygenic)

• 1% of population carries gene mutation (monogenic)

Lipoprotein particles

macromolecules formed by• fat• protein (apolipoprotein, apoprotein)

apo A → HDL, chylomicronsapo B → LDL, VLDL, chylomicronsapo C → chylomicrons, VLDL, LDL, HDLapo E → chylomicrons, VLDL, LDL, HDL

alleles 2, 3, 4

Lipoprotein particles

The compartment of production:apo A intestine, liverapo B - apo B-48 intestine

- apo B-100 liverapo C liverapo E liver

Lipoprotein particles

Lipoprotein particles

apo(a)apo B-100 + apo(a) form the lipoprotein Lp(a)

The individual isoforms of apo(a) present an important factor determinative the concentration of Lp(a), while between the size of isoprotein apo(a) and the concentration of Lp(a) is a reversal relation.

Predisposition to atherosclerosis

1) decreased level of apoA2) increased level of apoB and

apo(a) - small molecules3) increased level of apoE4

Monogenic form

Familial hypercholesterolemia• autosomal dominant disease• in 5% of myocardial infarction patients under 60y.• cause: dysfunction of LDL receptors (gene on 19p)• variable expressivity

- allelic heterogeneity - 300 mutations in the gene- locus heterogeneity – apoB gene

Familial hypercholesterolemia

Heterozygotes: occur with a frequency of 1 : 500have elevated serum cholesterol 7-10 mmol/l

up to the age of 30 – manifest clinical symptoms of HLPup to the age of 50 – manifest cardiovascular diseasesHomozygotes: occur with a frequency of 1 : 1 000 000

have very high serum cholesterol 15-30 mmol/lin childhood – manifest heart failuresup to the age of 20 – die of coronary artery disease

Gene dosage of LDL receptorin dependence on concentration of cholesterol

Various mutations of the LDL receptor gene are grouped into five functional classes:

Class 1 – accounting for about 20% of the total, do not produce any detectable LDL receptor protein (null alleles)

Class 2 – block the transport of the nascent LDL receptor protein from the endoplasmic reticulum to the Golgi apparatus

Class 3 – encode receptors that reach the cell surface, but fail to bind ligand

Class 4 – encode receptors that reach the cell surface and bind LDL, but are not localized to clathrin-coated pits and fail to internalize bound LDL

Class 5 – encode receptors that bind and internalize LDL receptor in coated pits, but fail to release the ligand in endosomes and fail to recycle back to the cell surface (recycling – defective mutants)

Biological role of LDL receptor in the celland 5 classes of its mutations

The structure of gene for LDL receptorwith localization of its mutations

Xanthoma of Achilles tendon

Comparison of severity of symptomsin homozygotes (hands) and in heterozygotes (legs)

Affection of FH course by sex

Use of resin and inhibitor of HMG-CoA reductase

in therapy of FH

Heritability of type 2 diabetes

• in 80-90% of population is a tight balanced state between genetic and environmental factors (multifactorial)

• 5-10% of population has a considerable genetic predisposition (polygenic)

• 5-10% of population has a considerable genetic resistance (polygenic)

• 1% of population carries gene mutation (monogenic)

Risk factors of type 2 diabetes

Insulin secretion disorder• transcription factor 7 - like 2 gene (TCF7L2 gene)• genes of cell cycle regulation • genes for development of liver and pancreas • genes for apoptosis• genes for ion channels/transporters (K+, Ca2+ / Zn2+)Insulin resistance• fat mass and obesity-associated gene (FTO gene)• peroxisome proliferator-activated receptor gamma gene

(PPARG gene) – transcription factor for binding fatty acids, prostaglandins, thiazolidinediones

Monogenic forms

MODYneonatal diabetes– permanent

– transient- kalium inward rectifier 6.2 KIR6.2 (KCNJ11 gene) - sulfonylurea receptor SUR1 (ABCC8 gene)diabetes with deafness- mitochondrial DNA mutations

MODY(MATURITY–ONSET DIABETES OF THE YOUNG)

• Autosomal dominant type of heredity• Onset at least in one family member up to the age

of 25• Adjustment of hyperglycemia fasting

at least two years without insulin• Non-ketosis diabetes• Disorder of insulin secretion without dysfunction

Mutations in the gene coding glucokinase

- glucokinase, GCK-MODY (chromosome 7 p)• this enzyme changes glucose into glucose-6-

phosphate, which stimulates the -cells to an insulin secretion glucokinase = glucose sensor

• diabetes with mild course without complications

Mutations in the genes coding transcription factors

hepatocyte nuclear factor-1, HNF-1, HNF1A-MODY(chromosome 12 q), the most frequent form

hepatocyte nuclear factor-4, HNF-4, HNF4A-MODYhepatocyte nuclear factor-1β, HNF-1β, HNF1B-MODYinsulin promoter factor, IPF1, IPF1-

MODYinsulin transcription factor NEUROD1, NEUROD1-MODYinsulin transcription factor KLF11, KLF11-MODY

(KLF11 = Krüppel-like zinc finger 11)

Literature - basicLiterature - basicGenetics in Medicine, sixth edition, revised reprintThompson & ThompsonSaunders, 2004

Chapter 11: Lessons from the hemoglobinopathiespages 181 – 202Chapter 15: Genetics of D.with Complex Inheritancepages 289 – 310Clinical Case Studies: 9, 17, 21, 28, 30

Literature - additionalLiterature - additional

Medical Genetics at a Glance, second edition,Dorian J. Pritchard & Bruce R. KorfBlackwell Publishing, 2008

Part 2: Medical genetics 30-32pages 76 – 83