What makes some diseases so complex, and what can we do about it?
--
Your DNA is like a receipt given to you by history. It’s the product of thousands of years of evolution through mutation and environmental adaptation. Every purchase on that receipt is a genotype and they all amount to a total of you. This total would be your phenotype, the physical expression of your genetic information into visible characteristics and traits making you who you are.
So why does this matter?
By studying someone’s genes it’s very easy to predict simple features like what colour their eyes will be. These follow what are known as Mendelian inheritance patterns or monogenic inheritance. The problem is when trying to predict more important stuff like disease, things get a bit more “complex” (because why wouldn’t they). This is known as multifactorial or complex inheritance because it involves multiple genes interacting to produce a specific trait. The majority of common diseases such as diabetes, cancer or coronary heart disease follow these multifactorial forms of inheritance.
If scientists are able to better understand the interactions that cause complex diseases to develop, it would make disease prognosis, diagnoses and treatment through genetic engineering way more effective. This means that scientist could be able to predict the future of your health and determine what diseases you could contract, just by studying your DNA.
Rundown of Mendelian inheritance
Gregor Mendel was a botanist, teacher, monk, scientist and an overall cool guy who’s now known as the father of genetics. He wanted to get a better understanding of how our traits were passed down through generations, so he did what any normal person would do and decided to dedicate 8 years of his life to breeding pea plants. Through the hybridization of different plants with different traits, Mendel came up with 3 laws of inheritance.
- Law of segregation of genes: Each organism contains 2 alleles for each gene (can be different or the same), these alleles separate during meiosis when being passed down to offspring.
- Law of independent assortment: Alleles for different traits are passed independently of one another.
- Law of dominance: Recessive alleles are masked by dominant alleles. The only way recessive alleles are expressed is if they’re paired with other recessive alleles.
His discoveries were revolutionary at a time when no one really understood genetics. Some disease’s such as cystic fibrosis and Huntington’s were found to move through families following Mendel’s laws of inheritance.
All diseases that follow Mendelian inheritance are passed down in two ways depending on which chromosomes they occur on;
- A disease can be autosomal which means it’s present in chromosome other than the sex chromosomes. Therefore, it is inherited by all children the same way regardless of their gender.
- A disease can be x-linked meaning it’s present in the sex chromosomes of the parents: XY for men, XX for women. X-linked disease follows a specific inheritance pattern depending on the parent and sex of the child.
Today, however, we know that less than 10% of diseases are linked to a single allele and most are affected by multiple factors across several different genes. We call these complex diseases.
What factors play into complex inheritance
Interactions of single genotypes together to decide your phenotypes
Consider how tall you are in comparison to your parents. It is very unlikely that you end up with the same exact height as one of them or even the median of their heights. If that was the case, generations of breeding would ultimately lead to all humans being the same height. People don’t get a “tall” gene or a “short” gene, instead, height follows a bell curve pattern with a higher concentration of people being in the middle. Height is one of the best examples of a polygenic trait that we know. There is no allele or gene telling your body to grow to 6 feet tall and stop. There is, however, a gene controlling how the vertebral disks in your spine develop or how strong your back muscles can get. These 2 traits plus an estimated 398 more are all separate genotypes that interact with each other to form the phenotype which is your height.
If the disease runs in your family, you could be susceptible too
Genetic predisposition in terms of complex disease refers to an increased likelihood, not a guarantee, of someone getting a disease. When looking back at past generations in your family, seeing a pattern of a specific disease most likely means that you have a combination of genes known to promote this disease. An example would be type 1 diabetes which is a disease that’s prevalent in people of younger age. Type 1 diabetes is considered an autoimmune disease and can be caused by having certain variants in genes coding your immune system which are most likely passed down from a parent.
The way you live can change your chances of disease
Aside from looking at genes, examining someone’s lifestyle and how old they are can also give an indication of the cause of a disease. Let’s take for example an individual in his late 40s who rarely exercises, and consumes a lot of saturated fats. This combination of age, unhealthy diet and low activity would most likely result in coronary heart disease. Even under the assumption that they had no genetic predisposition to the disease, their lifestyle choices had a massive impact. Lifestyle choices aren’t just limited to food and exercise though. Things such as the environment where you live, i.e city with lots of pollution all play a role in determining disease.
New mutations always occur in DNA
Our DNA isn’t as reliable as many of us think it is. Every person born has millions of variances in their genetic code that differs from the general population. Some of these are passed down in families but new variances known as de novo mutations can occur in children while not existing in parents. Genetic mutations variants can come in 2 forms SNVs and CNVs;
SNVs — Single nucleotide variations are those that occur in a single base pair. When these SNVs occur in more than 1% of the population, they’re called single nucleotide polymorphisms (SNPs or snips).
CNVs — Copy number variants occur in a large number of base pairs usually between 1000 base pairs to millions of base pairs long.
These two forms of mutations can occur in different ways in a genome. CNVs are mainly associated with deletion and duplication mutations where large parts of DNA are deleted or duplicated in a genome. SNVs can be inserted or deleted which causes missense, nonsense, and frameshift mutations. The location where these mutations occur determines what effect they will have.
Putting the pieces together and understanding complex disease
To understand how each of these factors come together to cause a disease we need thoroughly map and analyze the genome. The mapping is done through the use of various NGS techniques such as Illumina sequencing and 454 sequencing.
Illumina’s technique uses fluorescent attachments to each base pair to help identify them — Slower but more accurate
The DNA is first split into fragments of ~600 bases where they’re attached to adaptors. Through incubation, the DNA is made into a single strand so it can bind to primers on a flow cell (a glass slide with channels for DNA sequencing). The DNA strands then cluster and go through a process called bridge amplification that readies each strand for sequencing . A “read” process starts where the bases on the strands are attached to a fluorescent complementary base that can be read. This process is called sequencing by synthesis.
454 sequencing techniques rely on light intensity rather than colour — Faster but less accurate with repeated sequences (ex. AAAA)
The 454 sequencing process is efficient to the point that it can sequence a whole genome in 3 days(1 billion bp a day). The DNA is split into fragments around 600 bases as well and each strand is then connected to 2 types of adaptors. Resin beads with complementary adaptors are added to the DNA and connect to the strands. The enzyme DNA polymerase is used to amplify(make more of) these strands in polymerase chain reaction (PCR) machines. When these strand clusters are placed into wells and washed with different bases (A, C, T, G), they bind with the complementary bases giving of light. The intensity of that light determines the DNA sequence.
To analyze all this DNA that’s sequenced, scientists use Genome-wide association studies (GWAS)
Genome-wide association studies take the sequences from a large number of sequenced genomes and compares them with each other. The comparison helps identify common SNPs that are correlated with a specific disease as a way of determining what genetic combinations increases the risk of developing that disease. The studies also help pinpoint the SNPs location on your genome so that doctors know where to look in the next patient. GWAS have already been used to link some genes such as the HLA-DQA1, HLA-DQB1, and HLA-DRB1, genes to type 1 diabetes.
Key takeaways
- Some disease or traits are inherited through Mendelian inheritance patterns
- Complex disease takes into account a variety of factors like family history and lifestyle. These factors fit together like pieces in a puzzle to produce the final disease.
- To understand these complex diseases, NGS techniques can be used for accurate sequencing.
- GWAS are used to compare the sequenced DNA and identify SNPs.
- By interpreting complex disease, scientists can predict the future of your health.
