100,000 Genomes Project

A project initiated by the UK government in 2013 that aims to sequence 100,000 genomes from around 70,000
people in England with either rare diseases or cancer (www.genomicsengland.co.uk).

Alignment
The process of using a reference genome to assist with piecing a genome back together following sequencing
of DNA fragments.

Allele
Alternate forms of a gene at the same locus (position on a chromosome).

Amino acids
The chemical building blocks of which proteins are made. There are 20 different types of amino acids which
can combine in various forms to produce the many different proteins in our bodies.

Artefact
Something that does not represent the true biological material or function, but results from a technical, often
artificial, process.

Assembly
The process of piecing back together DNA sequence reads from fragments to create one readable genome
sequence.

Autosomes
Any of the 22 nuclear chromosomes other than the sex chromosomes.

BAM file
A BAM file (.bam) is the binary version of a SAM file. This is a compressed version of the SAM file that can be
read faster on computers and takes up less storage space.

Bases
Components of DNA or RNA. In DNA there are four chemical bases: adenine (A), guanine (G), thymine (T) and
cytosine (C). In RNA the bases are identical except for thymine which is replaced with uracil (U).

Bioinformatician
A scientist who applies computer science and information technology to biological problems, for example by
writing data analysis algorithms and managing data storage.

Catalysis
The acceleration of a chemical reaction.

Cell
The basic structural and functional unit of living things. In animals, cells consist of the nucleus and cytoplasm
which contains the cellular organelles surrounded by a membrane.

Cell cycle
A series of regulated stages that a cell passes through when it undergoes cell division. This involves the
duplication of all the cellular contents (including DNA replication) followed by separation into two identical
daughter cells.

Cell membrane
The outer casing of the cytoplasm of a cell, which allows controlled movement of materials in and out.
Centromeres
A region of the chromosome by which sister chromatids are linked during meiosis and mitosis. Chromosomes
attach to the mitotic spindle via the centromere during cell division.

Chromatids
Either of the two full-length DNA molecules produced by replicating a chromosome. Before DNA replication
each chromosome is made up of only one chromatid. After DNA replication, each chromosome is made up of
two chromatids, referred to as sister chromatids.

Chromosomes
Tightly packaged bundles of DNA plus associated proteins. Nearly all human cells have a set of 46
chromosomes, identified as 23 pairs; 22 pairs are autosomes with the 23rd pair the sex chromosomes.

Clinical exome
A test that looks at the protein-coding regions of the genome that have a clinical association (are known to be
associated with disease).

Codon
A sequence of three bases within DNA or RNA that encode for a particular amino acid - that is, they contain the
instructions for the placement of a particular amino acid when producing a polypeptide.

Coincidental findings
A genetic change found during sequencing that is thought to be both a pertinent finding (relevant to the
clinical question) and known to cause another, unrelated condition.

Daughter cells
Genetically identical cells formed when a cell undergoes division by mitosis.

Deoxyribonucleic acid (DNA)

The chemical that contains, or encodes, genetic information. DNA is made up of four different chemical bases
known as A (adenine), C (cytosine), G (guanine) and T (thymine).

Diploid
A cell containing two copies of each chromosome is referred to as a diploid cell; human somatic cells are
diploid: they contain 46 chromosomes, 22 pairs of autosomes and 2 sex chromosomes.

Direct-to-consumer testing
Commercially available services that provide genetic testing outside of the medical environment.

Disease-modifying variants
A type of mutation that contributes towards a disease phenotype (clinical signs and symptoms), but is not
causative on its own.

DNA ligase
An enzyme that sticks DNA fragments together. Involved in DNA repair and replication.

DNA polymerase
A type of enzyme that is able to synthesise DNA by chemically joining together nucleotides

Encode
To specify the genetic code for a protein. For example, there is a gene that encodes for the dystrophin
protein.
Enzyme
A type of protein that catalyses chemical reactions within an organism.

Exome
The 2% of the genome responsible for coding for proteins.

Exons
Sections within genes that are included in the final processed mRNA, and include the protein coding
sequences.

FASTA file
A raw text file representing DNA bases produced by DNA sequencing.

FASTQ file
A modified version of the FASTA file that also includes information about the quality of the sequencing data.

Gamete
An egg or a sperm.

Gene
A segment of DNA that encodes for a particular polypeptide. That is, the DNA sequence that contains the
biological instructions for the production of a polypeptide chain, usually a specific protein or component of a
protein.

Genetic counselling
The process of helping people understand and adapt to the genetic, medical, psychological and familial
implications of genetic contributions to disease.

Genetic recombination
The exchange of genetic material either between or within chromosomes which occurs during meiosis.

Genetic/genomic variation
Differences between the genetic sequences of individuals.

Genome
An organism's complete genetic material, including both genes that provide the instructions for producing
proteins (2%) and the non-coding sequences (98%).

Genomics
The study of the genomes of individuals and organisms, looking at both the coding and non-coding regions.
This term is also used when talking about related laboratory and bioinformatic techniques. In humans, the
study of genomics has a focus on areas of the genome associated with health and disease.

Genotype
The DNA sequence of an organism or individual, which determines (along with environmental influences) the
specific characteristics (phenotype) of that organism or person.

Germ cells
The precursor to gametes. Variation can occur in germ cells (known as germline variation/mutation).

Germline variant
A variant present at the point of conception. The variant is therefore present in every cell of that individual
and can be passed on to the next generation.
Haploid
Containing one copy of each chromosome pair. Human gametes (egg and sperm cells) are haploid, containing
22 autosomes and one sex chromosome.

Haplotype
The arrangement of DNA sequence variants along a single chromosome.

Heterozygosity
The presence of two different alleles of the same gene within an individuals genome.

Homologous chromosomes
Two chromosomes in a pair - normally one inherited from the mother and one from the father. For example
the two copies of Chromosome 1 in a cell would be referred to as homologous chromosomes.

Human Genome Project

An international research project that was the first to determine the complete sequence of the human
genome, launched in 1990 and completed in 2003.

Immunohistochemistry
A method of detecting the presence of a protein in a particular tissue.

In silico predictors
Computer software that predicts the impact of a given variant on the resultant protein.

Incidental findings
Findings from genome sequencing that do not relate to the clinical question. Can also be known as secondary
findings.

Information governance
A framework of best practice regarding the handling of sensitive data. In the health setting this includes
patient identifying details.

Interphase
The stage of the cell cycle when the cell grows and DNA replicates ready for mitosis.

Introns
Non-coding sections of a gene that are removed from the final RNA transcript before translation.

Karyotyping
Profiling a persons chromosomes to look at their appearance and number

Locus
A specific position on a chromosome (plural: loci).

Meiosis
A process of cell division that produces four cells, each with half the full complement of DNA. The purpose of
meiosis is to produce gametes (eggs and sperm cells).

Messenger RNA (mRNA)

A type of RNA that carries genetic information from the nucleus to the ribosome in order to make proteins.

Microarray
A method of measuring gene expression or performing genotyping. Also known as a DNA chip or biochip.
Mitochondria
Plural of mitochondrion. Organelles found within the cell cytoplasm that are responsible for energy
production. Contains a small genome of about 16,000 bases encoding 37 genes. This DNA is referred to as
mitochondrial DNA or mtDNA.

Mitosis
A process of cell division that results in two daughter cells, each with the full complement of DNA.

Mitotic spindle
A complex of tube-like structures that extend from one side of the cell to another and attach to chromosomes
via their centromeres during mitosis.

Mutation (gene variant)

Any difference between the sequence of a gene in the individual genome being sequenced and the normal
sequence(s) held in the reference genome. This may be disease causing, where the mutation (or gene variant)
causes the gene or gene product to function differently or cease to function. Also (more acceptably) known as
variation.

Multi-disciplinary team
A team of experts who, using discussion, debate and current research, come to a consensus about what to
report back to a patient.

Next generation sequencing (NGS)

An umbrella term given to describe modern high-throughput DNA sequencing techniques that have emerged
since Sanger sequencing.

Nuclear envelope
The membrane that surrounds the nucleus.

Nucleotide
The molecules that serve as the building blocks of DNA and RNA. Nucleotides consist of one nitrogenous base -
adenine, cytosine, guanine, or thymine (uracil in RNA) - a sugar (deoxyribose in DNA, ribose in RNA) and a
phosphate group.

Nucleus
A structure found within most cells that contains an entire copy of the organisms genetic information.

Off-target effects
When a drug has effects other than on its target within the body - may induce side effects.

Organelle
A small, specialised component of the cell with a specific function - eg the nucleus.

Panel testing
A test which looks at a curated set of genes known to be associated with the development of the condition or
collection of clinical symptoms under investigation.

Pathogenic
Disease causing.

Pathogens
Disease-causing organisms.
Personalised medicine
Medicine targeted towards an individual (or group of individuals), which uses knowledge of genetic,
environmental and lifestyle factors to determine suitable methods of prevention, diagnosis and treatment of
disease. Also known as stratified or precision medicine.

Pertinent findings
The findings from genome sequencing that directly relate to the clinical question/disease being investigated.
Also known as primary findings or main findings.

Pharmacodynamics
The effects of a drug on its target within the body.

Pharmacogenomics
The use of genetic and genomic information to tailor pharmaceutical treatment to an individual.

Pharmacokinetics
How a drug is distributed and metabolised in the body.

Phenocopy
A phenotype present in a family member when the underlying cause of that phenotype is different from the
cause of that clinical condition in other family members. For example a woman in the family who develops
breast cancer but does not have the BRCA1 variant found in other affected family members.

Phenotype
An organisms observable physical and biochemical characteristics (in humans, often the observed signs and
symptoms of a condition); directly influenced by the genotype (genetic factor) and/or environment.

Polymerase chain reaction

A method of copying a region of DNA. In the context of whole genome sequencing used in the library-
preparation phase of DNA sequencing.

Polymorphisms
Genetic variants found in a significant proportion of the population (usually 1% of people) that are not thought
to be associated with disease.

Polypeptide
A chain of amino acids.

Predictive testing
Also referred to a presymptomatic testing. A type of genetic test used to determine if an asymptomatic
individual (someone who isnt presenting with any clinical signs or symptoms of a genetic condition) has a
gene variant which may cause disease in the future.

Protein
A large molecule composed of one or more chains of amino acids, the sequence of which is determined by
DNA. The human body has over 100,000 different proteins performing many different functions.

Read
In next generation sequencing, a read refers to the DNA sequence from one fragment (a small section of DNA).

Read depth
The number of times a particular base is represented within all the reads from sequencing. The higher the read
depth, the more confidence scientists can have in identifying a base (known as base calling).
Read length
The number of bases that are read at one time (that is the number of letters that will appear in each read).
This differs between technologies, so optimum fragment length varies.

Recessive allele
A gene variant in one copy of a pair of genes that will not affect the individual.

Reference genome
An established normal genetic sequence for a particular organism with which other sequenced genomes can
be compared.

Ribonucleic acid (RNA)

Chemically similar to DNA but a single-stranded molecule. RNA is made up of four chemical bases, known as A
(adenine), C (cytosine), G (guanine) and U (uracil). There are a number of different types of RNA, one of which,
messenger RNA (mRNA), serves as a temporary copy of the information stored in the DNA.

Ribosomes
Structures found within the cell cytoplasm that are the site of protein synthesis.

Sanger sequencing
A sequencing method that involves incorporation of chain-terminating nucleotides (that is nucleotides that
stop the sequencing reaction) into a DNA strand complementary to a single-stranded DNA template. The
chain-terminating nucleotides are labelled (radioactive or fluorescent labelled) and the sequencing machine
can read the label and determine the DNA sequence.

Secondary findings
Clinically significant findings from genome sequencing that do not relate to the original clinical
question/disease. Also known as additional looked for findings or opportunistic screening.

Segregation studies
A type of study to identify or confirm the pattern of inheritance of a disease-causing variant within a family.
Usually only carried out in clinically affected individuals, so as to avoid undertaking unsolicited predictive
testing in unaffected relatives.

Semiconservative replication
The mechanism by which DNA is replicated in cells; results in DNA with one original strand on DNA and one
new strand of DNA.

Sequence Alignment/Map (SAM)

A plain text file produced from genome sequencing which includes the sequence of DNA reads as well as
information on where each sequence maps to on the reference genome.

Sex chromosome
The X and Y chromosomes. The sex chromosomes determine the biological sex of an individual: XX in women
and XY in men. The non-sex chromosomes (numbered 1 to 22) are known as the autosomes.

Single gene disorder

Condition caused by a genetic variant in a particular gene.

Single nucleotide polymorphisms (SNPs)

Genetic variation between individuals at a single nucleotide.

Sister chromatids
Either of the two identical copies (chromatids) formed by the replication of a single chromosome, joined
together by a common centromere.
Somatic cells
All cells in the body other than those that lead to the production of gametes.

Somatic variant
A variant arising in somatic cells which can therefore not be passed on to the next generation.

Splicing
The complex process by which introns are removed and exons rejoined to form a mature mRNA transcript.

Telomeres
Repetitive sequences of DNA at the end of each chromosome that act as protective caps to prevent
deterioration.

Transcription
The process whereby an mRNA molecule is produced from a specific region of the DNA.

Transfer RNA (tRNA)

A type of RNA that transports amino acids from the cell cytoplasm to the ribosome for protein synthesis.

Translation
The production of a polypeptide sequence from an mRNA transcript.

Truncating variant
A genetic variant which results in shorter version of the protein being produced.

Unanticipated incidental findings

Variants found from genome sequencing in genes that are unrelated to the disease being investigated.

US Food and Drug Administration (FDA)

A federal agency of the United States concerned with the regulation of food safety, tobacco, cosmetics,
pharmaceuticals and medical products and devices in the interests of public health.

Variant
Any difference between the sequence of a gene in the individual genome being sequenced and the normal
sequence(s) held in the reference genome. Variants can be harmless or disease causing (pathogenic).

Variant calling
Identifying differences between the sequenced genome and the reference genome.

Variant call file

File that holds information on the variants identified by genetic sequencing and the quality of the reading.

Variants of unknown significance (VUS)

Variants detected during sequencing, often for the first time, for which there is no or insufficient evidence
either for or against pathogenicity. Consequently the clinical impact is unknown.

Warfarin
A widely-used anticoagulant drug that reduces the risk of blood clotting.

Whole exome sequencing

Sequencing only the protein-coding regions of the genome (around 2% of all bases).

Whole genome sequencing (WGS)

A type of genetic sequencing that has the potential to sequence every DNA base in a genome.
X-linked
A pattern of inheritance for a genetic condition that occurs when a copy of a gene located on the X
chromosome has a genetic variant (or mutation).