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Introduction to human genetics and

genomics

Prof. Edit Buzs


Semmelweis University
Department of Genetics, Cell- and Immunobiology
Budapest

www.gsi.hu

oncogene16

Inherited features: Habsburg lip

Inherited features

Mary (1867-1953), and granddaughter Queen Elizabeth II

Edward VII (1841-1910) great-great-grandson Charles

King Edward I (1239-1307) anhis 21 td imes great-grandson


Prince William

King George VI (1895-1952) and great-grandson William

The Bach family

JS Bach and his sons Carl Philipp Emanuel, Johann Christian, Wilhelm Friedemann, and Johann Christoph Friedrich

The price of consanguinity in the Old Egypt


Tutanhamon
Cleft palate, club foot, missing bones of the foot

Cleopatra

Elongated
skull

The genetic material: DNA

The length of DNA

2m/nucleus

In our body the DNA is 651 times


longer than the distance of the
Earth and the Moon

The difference between the human and chimpanzee


genomes is 4% only

Homologous sequences

Homolog: DNA sequence from common ancestral gene


Ortholog: common ancestral gene, in different species, has conserved function
during evolution
Paralog: generated by duplication within the same genome, may gain new
functions

Difference between genomes

The genomes of two individuals show 99.5% identity if considering copy


number variations (CNVs).

Interindividual nucleotide differences


Single nucleotide polymorphisms (SNPs)

99.9% sequence identitity among individuals

CpG islands
Regions of DNA of at least 200 bp in length that have a G+C content >50%.
CpG islands are typically found in or near approximately 40% of promoters of
mammalian genes

cytosine phosphodiester bond

G
guanine

http://www.mad-cow.org/exon2.html

Do all the cells of our body contain the same


amount of DNA?

Somatic cells and germ cells differ


In somatic cells it also depends on the presence
and number of nuclei (e.g. RBC, skeletal muscle
cell)
Somatic cells also differ because of differ
(at different stages of the cell cycle)

Is the DNA sequence identical in all somatic cells?

No, in T cells and B cells it is different (somatic gene


rearrangement)

What does the DNA encode for?

RNAs and proteins


Lipids and carbohydrates are non-templated

Short reproduction time, high offspring number


made them valuable systems in genetics

E. coli

Drosophila

bakers yeast

Arabidopsis thaliana

Caenorhabditis Zebra fish

mouse

Basic terms

Genome: the complete genetic material of the cell


Genetics: science focusing on induvidual genes, the
inheritence and variability
Genomics: science focusing on the entire genome and
the interection of genes
Epigenetics: science focusing on inherited, however
not DNA sequence encoded changes of gene
expression

Building block s of DNA

nucleoside

32

nucleotide

P labeling (synthetic oligonucleotides, 3H timidine for the assessment of


proliferation)

1 DNA molecule = 2 polynucleotide chains

pyrimidine

purine

2x 3x109 base pairs/human somatic cells


bp (base pair)

DNA
5

DNA

The antisense or nonsense or non-coding strand:


it is the active strand that participates in
transcription of sense (5AUG 3) mRNA.
Single strands are written by convention 5-3.

What can we tell by the sequences?

RNA and DNA

The nucleosoal organization of the


DNA

The chromatin filament

The formation of chromosomes

The formation of chromosomes

Chromatin
(interphase)
Scaffold protein
(e.g.. topoisomerase
II)

Chromatin

Isolated from interphase nucleus


(30 nm thick)

Unpacked chromatin, shows nucleosomes

Cell cycle

c
c

Chromatin: in interphase (G1+S+G2)


Chromosome: at cell division

Chromatin chromosome
Pro

chromatin

Meta

Ana

Telo

chromatin

http://www.sciencedirect.com/science/article/pii/S0091679X08004238

chromatin chromosome

Chromosome

Chromosome

1 sister chromatid=
1 DNA molecules

2 DNA olecules

Chromosome

46 /human
somatic cell

Does the number of chromosomes tell much about


an organism?

ALAPFOGALMAK
Basic terms
Gene: the unit of inheritance, part of the DNA or RNA
Locus: location of a given gene on a chromosome
Allele: gene variant at a given locus
Wild type allele: the most frequent variant of a given gene in nature
Genotype: genetic composition characteristic for an individual or a locus
Phenotype: Measurable and observable features of a cell or and
individual

Homologous pair of chromosomes

paternal

maternal

23 pair/somatic cell

Homologous pair of chromosomes


paternal

maternal

Basic terms
Homozygote: identical alleles at the same loci of the chomosome pair
Heterozigote: different alleles at the same loci of the chomosome pair
Hemizigote: carries only a single copy of the gene
Dominant allele: a gene variant that phenotypically always results in a
given chracateristics (even in heterozygotes)
Recessive allele: a gene variant that manifests phenotypically in homoand hemizygotes only
Possible genotypes: AA, Aa, aa

Ploidy
Ploidy refers to the number of homologous chromosomes of a cell. If a
cell contains a single set of chromosomes only, then it is haploid, if it has two
sets of chromosomes, then it is a diploid one.

DNA replication

DNA replication

Cell division
MITOSIS

MEIOSIS

92 DNA

92 DNA

92 DNA

I.
46 DNA

II.
46 DNA

46 DNA

23-23 DNA

23-23 DNA

Gregor Mendel
(1822-1884)

Mendel investigated 7 pairs of characteristics

Mendels laws
Law of uniformity

1865

> 6000 monogenic human genetic


diseases following Mendelian
inheritance

49

The genome

Mitochondrial

Nuclear

The nuclear and mitochondrial genomes

The human genome

(coding)

Mb (megabase): 1 million bases

Repetitive sequences in the genome

The structure of the human genome

Transposons
Barbara McClintock
1983, Nobel prize

cut and paste

copy and paste

The structure of the eukaryote gene


downstream

Regulation of transcription

Chromatin

heterochromatin
euchromatin

Regulation of eukaryotic gene transcription

RNA polymerases

Transcription

Transcription

Figure 1 : Electron micrograph of nascent pre-mRNAsa.


EM of growing mRNAs in yeast show how transcription can be visualized in cells.
2002 Nature Publishing Group Dragon. F. et al. A large nucleolar U3 ribonucleoprotein
required for 18S

RNA maturation

The central dogma of gene expression

Alternative splicing

Alternative splicing

RNA splicing

Types of RNA molecules


mRNA

Extracellular RNAs

http://circres.ahajournals.org/content/110/3/483.figures-only

mRNA travels to the cytosol for translation

Codon and anticodon

The genetic code


1. It consists of triplets
2. Degenerated (redundant):
20 aa-64 triplet combinations
3 stop codon (TAA, TAG, TGA)

3. Comma-free, non-overlapping
4. Almost completely universal
5. Wobble effect

(Francis Crick)

6. Unambiguous
(1 codon encodes for 1 amino acid
only)

Wobbling effect

Posttranslational modifications

Posttranslational modifications

Milestones of the history of genetics

Rosalind
Franklin

1865
Gregor
Mendel:
genetika
trvnyei

Maurice
Wilkins

Cloning of the sheep, Dolly (1996)

Copy cat, 2002,


USA

2012, India

2008, Korea
2010, USA
2007, Canada

Human Genome Project

Number of human genes is


~22000-30000

http://www.nature.com/encode/

Encyclopedia of DNA Elements (ENCODE) Project


(2003-2012)

Major result:
Presumably a much larger proportion of the human DNA is
active than what we thought previously:
the majority of the non-coding regions participate in regulation
of the expression of the coding 1%

Human genome + human microbial


genome (microbiome)

min. 10x bacterial cells

TOOLS
PCR: 1 million fold amplification of
segments of DNA within a few hours

Restriction endonucleases: targeted


cleavage of the DNA and generation of
recombinant DNA

CRISPR CAS9 genome editing in a fast and simple


manner

guide RNA+
CAS9 enzyme