Genes and proteins in Health and Disease

What you should know Proteins are held in a three dimensional shape by peptide bonds, hydrogen bonds, interactions between individual amino acids. Polypeptide chains fold to form the three dimensional shape of the protein.

PROTEIN - STRUCTURE AND FUNCTION

PROTEIN STRUCTURE Proteins are made from long chains of amino acid molecules. The amino acids are linked by peptide bonds. A chain of amino acids is called a polypeptide chain

PROTEIN PRIMARY STRUCTURE The primary structure of a protein is the polypeptide chain of amino acids

PROTEIN SECONDARY STRUCTURE Weak hydrogen bonds form between various amino acids. This causes the polypeptide chain to become coiled into an  helix (coiled) or folded into a  pleated sheet (folded)

PROTEIN TERTIARY STRUCTURE The tertiary structure is the final structure of the protein due to hydrogen bonding and sulphide bonding between amino acids. tertiary structure can form either fibrous proteins or globular proteins.

PROTEIN QUARTERNARY STRUCTURE Quarternary structure is formed when several polypeptides become bonded together

FIBROUS PROTEIN Formed when several polypeptide chains are bonded together in long parallel strands examples include collagen (skin), keratin (hair) and actin and myosin (muscle)

GLOBULAR PROTEINS Look like a tangled ball of string Enzymes, hormones and antibodies are all globular proteins

CONJUGATED PROTEIN Contains polypeptide chains and a non- protein part E.g. haemoglobin consists of 4 polypeptide chains and 4 iron atoms

Functions of proteins Enzymes e.g. amylase Structural proteins e.g. a component of the cell membrane Hormone e.g. insulin antibodies

Mutations- What you should know Mutations result in no protein or a faulty protein being expressed. Single gene mutations involve the alteration of a DNA nucleotide sequence as a result of the substitution, insertion or deletion of nucleotides. Single-nucleotide substitutions include: missense, nonsense and splice-site mutations. Nucleotide insertions or deletions result in frame-shift mutations or an expansion of a nucleotide sequence repeat. The effect of these mutations on the structure and function of the protein synthesised and the resulting effects on health. Chromosome structure mutations – deletion; duplication; translocation. The substantial changes in chromosome mutations often make them lethal.

What is a mutation? It’s a change in the structure or composition of an organisms’ DNA This can lead to no protein or a faulty protein being expressed

MUTATIONS Occur naturally in every population They can occur spontaneously They cause a change in the organism’s DNA An individual with a mutation is termed a mutant The frequency of mutations can be increased by mutagenic agents e.g. chemicals & radiation

EXAMPLES Polydactyly – presence of extra finger or toes Liam Gallagher and Marilyn Monroe!!

Single Gene Mutations Changes in one or more nucleotides in the DNA of the cell -Substitution -Insertion -Deletion

Substitution Mutations One nucleotide is replaced with another Missense- mutation ends up coding for wrong amino acid Nonsense- mutation causes codon to be replaced by STOP codon, so no amino acid produced Splice-site mutations- intron/exon splice is affected and an intron may be retained in error

Sickle Cell Anaemia

PKU Phenylketonuria phenylalanine tyrosine enzyme geneMUTATION

Insertion Mutations All amino acids altered The addition of one or more nucleotides into the DNA Codons in mRNA that appear after the mutation have changed as a result, the amino acids in the protein are also different A type of mutation which has this effect is called a frameshift mutation.

Deletion Mutations All amino acids altered The removal of one or more nucleotides from the DNA Making it another example of a frameshift mutation

Cystic Fibrosis

Point Mutations Any mutation involving a single nucleotide Could be substitution, insertion or deletion Minor changes to individual amino acids

Insertion and deletion mutations The loss or gain of 1 or 2 nucleotides causes the affected codon and all of the codons that follow to be misread. This leads to a very different and often non-functional protein product. Frameshift Mutations

Nucleotide sequence repeat expansion Results in extra copies of a particular amino acid It may repeat so often that the gene may be silenced and fails to express any protein at all Fragile X syndrome Huntingdon’s disease

Fragile X syndrome Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females

Huntingdon's disease Huntington's disease is an inherited disease of the brain that damages certain brain cells The disease damages some of the nerve cells in the brain, causing deterioration and gradual loss of function of these areas of the brain. This can affect movement, cognition (perception, awareness, thinking, judgement) and behaviour.

Single nucleotide substitutions include: A nonsense mutation is the substitution of a single base pair that leads to the appearance of a stop codon where previously there was a codon specifying an amino acid. The presence of this premature stop codon results in the production of a shortened, and likely non-functional, protein. Can result in sickle cell disease and PKU

A missense mutation is when the change of a single base pair causes the substitution of a different amino acid in the resulting protein. This amino acid substitution may have no effect, or it may render the protein non- functional. Can result in Duchenne muscular dystrophy.

Splice-site mutations occur within genes in the non-coding regions (introns) just next to the coding regions (exons). Before mRNA leaves the nucleus, the introns are removed and the exons are joined together (splicing). A mutation that alters the specific sequence denoting the site at which the splicing of an intron takes place can lead to retention of large segments of intronic DNA by the mRNA, or to entire exons being spliced out of the mRNA. These changes could result in production of a non-functional protein. Can result in beta thalassemia. Beta thalassemia is a blood disorder that reduces the production of hemoglobin. Hemoglobin is the iron- containing protein in red blood cells that carries oxygen to cells throughout the body. In people with beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body. Affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, fatigue, and more serious complications. People with beta thalassemia are at an increased risk of developing abnormal blood clots.

Chromosome Mutations Chromosome mutations occur during cell division, both in mitosis or meiosis can cause a change in either the number or structure of the chromosomes Deletion Duplication Translocation A mutation to a chromosome usually involves a substantial change to its structure This type of mutation can be lethal

Deletion Deleted area a segment of a chromosome, and its associated genes, is lost The effect depends on exactly which sections of DNA are lost and varies from no effect to being fatal

Example of Deletion Mutation The structure of a chromosome can be altered by: –Deletion resulting in the loss of a segment of the chromosome –Can result in Cri-du-chat syndrome (deletion of part of the short arm of chromosome 5) The name of this syndrome is French for "cry of the cat," referring to the distinctive cry of children with this disorder. Another example of a Deletion Mutation effect is ‘Williams Syndrome’

Duplication The repeat of a segment of a chromosome Extra genetic material is present as genes are repeated on the same chromosome Can cause detrimental effects e.g. Cancer

Translocation Part of chromosome 22 has been translocated to chromosome 9 Segments of 2 (or more) chromosomes are exchanged Or an entire chromosome is attached to another E.g. chronic myeloid leukaemia

This karyotype is from a woman with 45 chromosomes and a translocation between chromosomes 13 and 14 No abnormal symptoms detected!

Chronic myeloid leukaemia translocation (9;22) Chronic myeloid leukaemia (CML) is a cancer of blood- forming cells in the bone marrow. Abnormal cells gradually fill the bone marrow and spill into the bloodstream. The disease typically develops very slowly and symptoms such as anaemia, bleeding problems or infections may not occur for years after the disease starts. 46,XYt(9;22)

Familial Down’s syndrome The vast majority of Down’s syndrome cases results from an extra copy of chromosome 21, however in about 5% of cases one parent has the majority of chromosome 21 translocated to chromosome 14 resulting in Familial Down’s syndrome

Chromosome mutations overview:

Mutations- you should know Mutations result in no protein or a faulty protein being expressed. Single gene mutations involve the alteration of a DNA nucleotide sequence as a result of the substitution, insertion or deletion of nucleotides. Single-nucleotide substitutions include: missense, nonsense and splice-site mutations. Nucleotide insertions or deletions result in frame-shift mutations or an expansion of a nucleotide sequence repeat. The effect of these mutations on the structure and function of the protein synthesised and the resulting effects on health. Chromosome structure mutations – deletion; duplication; translocation. The substantial changes in chromosome mutations often make them lethal.