3.7.4 Heterogeneity and phenotypes

Molecular and Genetic Heterogeneity

Molecular and genetic heterogeneity refers to the concept that a single disease can be caused by a variety of different genetic or molecular factors. This means that a disease can have multiple genetic or molecular origins, resulting in varying symptoms and progression even among individuals with the same diagnosis.

For example, a disease like Alzheimer’s can have several genetic and molecular causes, including mutations in specific genes, changes in the regulation of gene expression, and variations in the levels of specific proteins. This heterogeneity can lead to differences in the age of onset, symptoms, progression, and response to treatments (Habes, 2020).

There are several factors that contribute to molecular and genetic heterogeneity, including genetic mutations, epigenetic changes, and environmental factors. Understanding the molecular and genetic heterogeneity of diseases is important for developing more effective diagnoses, treatments, and preventive measures (Harrison, 2005).

Given the potential treatment consequences, the heterogeneity of molecular profiles presents a significant challenge in cancer, particularly in lung cancer. Heterogeneity refers to variations in the molecular makeup of cancer and can take different forms, such as intra-tumour heterogeneity, inter-patient variability, and patient-to-patient variability. Inter-patient variability is associated with genetic and phenotypic differences among people with the same type of cancer, which can help explain why different patients respond differently to treatments. Intra-tumour heterogeneity refers to the differences between the main tumour and its metastases, as well as the subclonal diversities of tumour cells found within a single tumour. This results in a variety of therapy responses for each patient with lung cancer due to the molecular heterogeneity between patients with the same histotype. The high degree of genetic variability between the primary lung tumour and its associated metastatic lesions also greatly influences the treatment environment for patients with lung cancer. Understanding the molecular heterogeneity of cancer is crucial for developing effective diagnoses, treatments, and preventive measures.

The phenomenon of genetic heterogeneity refers to the possibility that any one of a large number of alleles or non-allele alterations could be the source of a particular phenotype or genetic condition. This contrasts with pleiotropy, in which a single gene may result in a variety of phenotypic manifestations or illnesses.

Phenotypes and Genotypes

Phenotype: a collection of observable features and characteristics that result from the interaction of an individual’s genotype and the environment.

Endophenotype: is an intermediate phenotype with a closer connection to underlying genetics than the disorder in question.

Biotypes: are referred to when the organisms are sharing a specified genotype.

Epigenetics is the study of how your behaviour and environment can impact the way your genes function. Epigenetic alterations, unlike genetic changes, are reversible and do not alter your DNA sequence, but they can alter how your body reads a DNA sequence. Epigenetics involves non-sequence changes to both DNA and proteins. Environmental variables raise the risk of a variety of psychiatric diseases, and the same risk factors can raise the risk of many disorders.

Allelic diversity refers to the presence of several mutations in the same gene that may be linked to phenotypes in the biochemical or clinical realms that are remarkably similar or quite dissimilar. This is obviously important for identifying heterozygotes. For instance, since the S and D haemoglobins electrophorese similarly under standard conditions, individuals carrying the mutation for Haemoglobin-D will be incorrectly identified as carriers of the sickle-cell trait if a standard haemoglobin electrophoresis result (biochemical phenotype) is the only parameter used for sickle-cell trait identification.

References:

(1) Habes, M., Grothe, M.J., Tunc, B., McMillan, C., Wolk, D.A. and Davatzikos, C. (2020). Disentangling heterogeneity in Alzheimer’s disease and related dementias using data-driven methods. Biological psychiatry, [online] 88(1), pp.70–82. doi:https://doi.org/10.1016/j.biopsych.2020.01.016.

(2) Harrison, P. J., & Weinberger, D. R. (2005). The genetic and molecular heterogeneity of schizophrenia. Nat Rev Neurosci, 6(4), 341-50.