Introduction to Human Genetics

Chapter One

What is DNA?

• Deoxyribonucleic Acid:– String of nucleotides

• Nucleotides made up of three parts:

deoxyribose(a sugar)

OH

OH

HO-CH2

+ P –

– =

–

O

O

O

O -

-

-

phosphate

+

cyclic amine(base)

N

N

NucleotideOH

O-CH2P –

–

=

–O

O

O

-

-

N

N

DNA

O-CH2P –

–

=

–

O

O

O

-

N

N

O

O-CH2P –

–

=

–

O

O

O

-

N

N

O-CH2P –

–

=–

O

O

O

-

-

N

N

Sugar-Phosphate Backbone

(negatively charged)

Specific Bases

The Five Bases

• A = Adenine

• T = Thymine

• G = Guanine

• C = Cytosine

• RNA only:– U = Uracil (replaces T)

Structures of Bases

N

N

Pyrimidines

N

N

N

N

Purines N

N

N

N

CH3O O

O O O

O

NH2

NH2

N

N

N

N

NH2

A G

T U C

DNA

O-CH2P –

–

=

–

O

O

O

-

O

O-CH2P –

–

=

–

O

O

O

-

O-CH2P –

–

=–

O

O

O

-

- T

A

C

Sequence of DNAis order of the basesattached to backbone

Double Helix

• Sugar-Phosphate backbone is on outside

• Bases are inside - Hydrogen-bonding to opposing base on opposite strand

• Forming Base Pairs

Base Pairing

• Experiments showed:1. Two strands were always same distance

apart

2. Percentages of A always matched T, and G always matched C

• Therefore…1. A Purine must always be base paired to a

Pyrimidine

2. A = T, and G = C

3. Strands must be complementary

=

Summary of DNA

• String of Nucleotides

• deoxyribose Sugar-Phosphate backbone

• 4 Bases:– A, G are Pyrimidines– T, C are Purines– A = T– G = C

• Two complementary strands (double helix)

=

Central Dogma

dog·ma       P   Pronunciation Key  (dôg ma)n. pl. dog·mas or dog·ma·ta 1. A doctrine or a corpus of doctrines relating to matters such as morality and faith, set forth in an authoritative manner by a church. 2. An authoritative principle, belief, or statement of ideas or opinion, especially one considered to be absolutely true.

Central Dogma

DNA

RNA

Protein

Transcription

Translation

TranscriptionRNA polymerase

Double Stranded DNA

“Promoter” opens

initiation

elongation

termination

single stranded mRNA

Translation

AGAGCGGA.AUG.GCA.GAG.UGG.CUA.AGC.AUG.UCG.UGA.UCGAAUAAA MET.ALA.GLU.TRP.LEU.SER.MET.SER.STOP

...AGAGCGGAATGGCAGAGTGGCTAAGCATGTCGTGATCGAATAAA...

1 base codon - 41 = 4 possible amino acids

2 base codon - 42 = 16 possible amino acids

3 base codon - 43 = 64 possible amino acids

4 Nucleotides 20 amino acids

Translation

single stranded mRNA

tRNAamino acid

Codon (3 bases)}

The Genetic CodePhe

Leu

Leu

Val

Ile

Met

Ser

Pro

Thr

Ala

Tyr

Stop

His

Gln

Asn

Lys

Asp

Glu

Cys

Arg

Ser

Arg

Gly

StopTrp

UUUUUCUUAUUG

CUUCUCCUACUG

AUUAUCAUAAUG

GUUGUCGUAGUG

UCUUCCUCAUCG

CCUCCCCCACCG

ACUACCACAACG

GCUGCCGCAGCG

UAUUACUAAUAG

CAUCACCAACAG

AAUAACAAAAAG

GAUGACGAAGAG

UGUUGCUGAUGG

CGUCGCCGACGG

AGUAGCAGAAGG

GGUGGCGGAGGG

Translation

Note: Actually a different tRNA for each different codon

Proteins

• Protein Sequence = order of the amino acids

Sequence

Structure

Function

Central Dogma Summary

• DNA is in the nucleus of each cell• DNA encodes for RNA (transcription)• RNA encodes for Proteins (translation)• DNA and RNA are made of nucleotides• Protein is made of amino acids• A protein’s function is determined by it’s

structure, which is determined by it’s sequence

• Therefore…DNA encodes protein function

What is a gene anyway?• A gene is a small piece of DNA• It begins with a promoter

– This is region of sequence that tells RNA polymerase “start here”

– Also regulates amount of mRNA that is made

• Includes Introns and Exons– Introns are removed during transcription– Exons are the parts of the sequence that

become mRNA

• Also, gene has regulatory regions

Gene Structure

mRNA

protein

One gene = one protein

• Only not really:– Splice variants = form different proteins

– Different alleles = different versions of the same protein

– Polymorphisms; may change protein sequence or regulation of protein

– Mutations may destroy a protein, or change it’s normal function or expression

Genetic variance:

• Allele: Alternative form of one gene, usually form same protein, with slight changes, but same function

• Polymorphism: Usually a silent change (something that doesn’t affect the protein), that is often common in population

• Mutation: A change in the DNA sequence that will change the protein’s function or regulation, usually in a detrimental way

Sequence vs. Expression

• Genetic variances can affect:– Sequence of the gene

• May change the sequence of the protein• May be “silent”

– Level the gene is expressed • Amount of protein that will be made

– Where a gene is expressed• What cell type• What tissue• What time point in development

Chromosomes

• Chromosomes can carry thousands of genes– Made of DNA and proteins

• Human have 22 pairs of autosomal chromosomes– 1 is the largest, 22 is the smallest

• Humans have 1 pair of sex chromosomes– XY is male, XX is female – X inactivation in females

How are genes inherited?

• Genes are carried in the DNA• DNA is condensed into chromosomes• Each individual has two copies of every

chromosome• Sex cells (sperm or eggs) each have one

copy of every chromosome• Mating leads to one copy of every

chromosome coming from one parent and other copy coming from the other parent– Variances are mixed in offspring

Traits• Any distinguishing feature that can be

measured– Quantitatively (ex. height, weight)– Qualitatively (ex. disease status)

• Inherited Traits– Completely genetic

• Non-inherited Traits– Completely Environmental

• Complex Traits– Partially Genetic, partially environmental

Complex Traits

• Disorder that is proven heritable, yet has no clear mode of inheritance– Doesn’t follow Mendel’s laws

• More than one gene

• Interaction between genes

• Interaction between gene(s) and environment

Why Common Complex Disorders and Rare Mendelian Disorders?

• Evolution can act upon a single detrimental gene – negative selection

• Gene functions that are good for some things, but can be harmful in excess– ex: rational fear vs. anxiety disorders

• Normal alleles only predisposing – other mutations/environment present

Genotype vs. Phenotype

• Genotype = combination of alleles individual is carrying – Genes (which versions)

• Phenotype = measurable traits individual shows– Final Product

Applications:

• Selection– First use of genetics– What are some examples?

• Evolution– Tracing origins

• Forensics– What are some examples?

• Medical Care– Studying, treating, curing diseases

Next Class:

• Read Chapter Three• Homework – Chapter One Problems;

– Review: 1, 2, 4– Applied: 3, 4, 11, 14