Discover Artificial Intelligence

Review

An overview of artificial intelligence in the field of genomics

Khizra Maqsood1 · Hani Hagras1 · Nicolae Radu Zabet2

Received: 17 November 2023 / Accepted: 2 January 2024

© The Author(s) 2024  OPEN

Abstract
Artificial intelligence (AI) is revolutionizing many real-world applications in various domains. In the field of genomics,
multiple traditional machine-learning approaches have been used to understand the dynamics of genetic data. These
approaches provided acceptable predictions; however, these approaches are based on opaque-box AI algorithms which
are not able to provide the needed transparency to the community. Recently, the field of explainable artificial intelligence
has emerged to overcome the interpretation problem of opaque box models by aiming to provide complete transpar-
ency of the model and its prediction to the users especially in sensitive areas such as healthcare, finance, or security. This
paper highlights the need for eXplainable Artificial Intelligence (XAI) in the field of genomics and how the understand-
ing of genomic regions, specifically the non-coding regulatory region of genomes (i.e., enhancers), can help uncover
underlying molecular principles of disease states, in particular cancer in humans.

1 Introduction

In 1957, Francis Cricks proposed the central dogma of molecular biology which explains the flow of genetic information
in a living organism summarized in a pathway (Fig. 1) from DNA (Deoxyribonucleic Acid) to RNA (Ribonucleic Acid) and
from RNA to protein (a functional form of the DNA) [12]. DNA has double-helical strands containing four basic units called
nucleotides: Adenine (A), Thymine (T), Cytosine (C), and Guanine (G). The two strands of DNA are linked with a chemical
bond between bases; A is paired with T and C with G. The DNA base sequence contains all biological information to be
transcribed into a protein product. In living cells, DNA is organized in the form of chromosomes, which are further organ-
ized into segments of DNA called genes that encode for proteins (see Fig. 2). The sum of all genes or genetic material
that an organism possesses is known as the genome [15]. The field of life science that focuses on studying the genome
or genomic sequences of organisms is called genomics. The human genome possesses approximately 3 billion DNA base
pairs, and the field of human genomics aims to link the genome with molecular and physical characteristics [2]. It is a
data-driven science that involves high-throughput next-generation sequencing (NGS) technology development that
generates data on the whole genome of an organism. These sequencing techniques include whole exome sequencing
(WES), whole genome sequencing (WGS), as well as transcriptomic, chromatin, and epigenetic profiling.
In 2001, the completion of the Human Genome Project (HGP) was an important scientific development in the field
of genomics, by providing the reference of most of the human genome. Recent technological advances in long reads
have allowed for improved human genome reference by sequencing the remaining 8% of the human genome [30].
The sequencing of the whole genome allowed a better understanding of the genetic variation among the organisms

* Hani Hagras, [email protected]; * Nicolae Radu Zabet, [email protected] | 1The Computational Intelligence Centre, School
of Computer Science and Electronic Engineering, University of Essex, Colchester CO4 3SQ, UK. 2Blizard Institute, Barts and The London
School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.

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Fig. 1  The Central Dogma of

Molecular Biology: Genetic
information is transformed
from DNA to RNA in the
process of transcription. RNA
is then translated into the final
protein product, which have a
variety of functions

Fig. 2  The Nucleotide bases

make a chemical bond to form
a double helical structure
called DNA. Genetic mate-
rial is made up of DNA that is
tightly packed into chromo-
somes. Only a certain region
of DNA contains genes that
code for proteins

or even within the different cells, tissues, and disease states of an organism. The findings of the HGP suggested that
all humans are 99.9% genetically identical and only 0.01% variation in the human genome can make all humans
phenotypically different, such as their disease susceptibility, responses towards drugs, and physical traits (hair col-
our, eye colour, height, intelligence, etc.) [14]. One major aim of genomics is to identify the underlying changes or
mutations that may occur in DNA sequences to alter cellular processes and cause the disease states, usually done
through genome-wide association studies (GWAS) (see Fig. 3). It is worth noting that not all occuring mutations are
disease-causing; for example: not all single nucleotide polymorphisms (SNPs) (a single change in a base pair) or
indels (insertions or deletions of small pieces of DNA) change the DNA sequence coding for a protein (synonymous
mutations) or expression of the genes [18]. If we can identify which variation is linked to a specific disease, we will
be able to design better treatments, drugs, or even cures. McGuire et al. [26] reported that investigating genetic vari-
ation could improve our understanding of why certain people respond differently to the same medications. That is
where the personalized medicine concept comes, where pharmacogenomics can develop and prescribe personalized
medicine to an individual though understanding their genetic makeup.

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Fig. 3  A mutation has

been detected in the gene
sequence that is responsible
for the disease state. For com-
plete analysis, a genome-wide
association study is required

Cancer is one the most prevalent chronic diseases that caused by genome alteration. Including base substitutions,
deletions, rearrangements, or amplifications. The mechanisms of sequence alteration vary between different cancer types.
Furthermore, genomics also plays an important role in managing and understanding infectious diseases on both
population and individual levels [24]. In particular, it helps researchers identify and keep track of the emergence of
drug resistance in pathogenic organisms. For example, during the COVID-19 pandemic, genomics helped scientists
track virus (pathogens) transmission to understand how the strain was evolving to aid the development of effective
vaccines. Genomics is also enabling more targeted tests such as for rare disorders, tumour genome analysis, and non-
invasive prenatal screening. Furthermore, genomics has also revolutionized the field of agriculture by helping scientist
understand the genetic makeup of livestock and crops. Genomics will allow scientists to develop genetically modified
organisms (GMO) that can be pests resistant, tolerate harsh environmental conditions and increases yield. This is needed
to handle the challenges associated with the growing world population to ensure food security [32]. Biodiversity can also
be understood by comparing the genomes of various species and look at the underlying principle of the evolutionary
history of organisms and their adaption to different environmental conditions.

2 Cancer genomics

Cancer develops because of alterations or mutations that occur in the DNA sequence of genes that regulate cell survival,
division, or other hallmarks of the transformed phenotype, resulting in the development of uncontrollable cell growth
and the spread of abnormal cells. These cells can acquire genetic mutations that affect normal cell growth mechanisms
and lead to formation of tumours. For several years researchers have been trying to understand the biological basis of
various cancers showing variable clinical outcomes. Genomics can provide insights into the underlying principles of
this heterogeneous and complex disease. Genomic studies help researchers identify multiple mutated genes that cause
cancer and these are called oncogenes. A common example is the TP53 gene, which is mutated in different cancers [42].
The use of NGS technologies can provide us with the whole genome profiling of a cancer patient, which can help in
identifying and understanding clinically relevant genetic variations that can be targeted for potential therapies. In 1998
the first molecular targeted drug was introduced based on comprehensive genomic profiling (CGP) called trastuzumab
in patients with ERBB2-overexpressed breast cancer. Since then, several novel targeted therapies have been discov-
ered including BRAF melanoma inhibitors, BCR/ABL chronic myeloid leukaemia inhibitors, and epidermal growth factor
receptor (EGFR) non-small cell lung cancer tyrosine kinase inhibitors which provided robust therapeutic responses [29].
Most large-scale genome projects such as the International Cancer Genome Consortium (ICGC) and The Cancer
Genome Atlas (TCGA) have mainly focused on cancer genome characterization. Through genetic variations that occur in
the coding part of the genome and have identified numerous novel mutations. However, only 2% of the human genome
is coding with the remaining 98% being non-coding and there being very limited information on how variations in the
non-coding part of the genome can affect the development of cancer [42]. Elliott & Larsson [16] reported that mutations
in the non-coding part of the genome are abundant, but their effects are so far poorly understood. Recent studies have
shown that variations in the non-coding regulatory region of the human genome are highly associated with disease
conditions. The identification and mechanisms of gene regulatory regions are not only important to understand the

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function of the genome, but they also help in the widening the understanding of disease causation and provide a better
overview of disease state. For example, a mutation in the regulatory region of the RB1 gene has been found to be a major
source of brain cancer glioblastoma [4]. Genes have multiple non-coding regulatory regions that include promoters,
activators, enhancers, and silencers. This paper will focus on enhancer regions, and why identifying and understanding
the mechanisms of enhancers is important in cancer.

3 Enhancers and cancer

Enhancers are non-regulatory elements responsible for controlling the transcription of one or more genes (Fig. 4). The
characterisation and identification of these regions is important in the context of human disease to determine disease
causation and aid in the development of novel drugs. Enhancers can activate expression of proximal or distal genes, the
latter function is important in chromosome looping and Topologically Associated Domains [10]. Enhancers are cell-type
specific and are located in different regions of the genome [6]. Recent studies have shown that enhancers are associ-
ated with several epigenetic markers, including histone modification signals such as H3K4me1/2/3 [11], H3K27ac [13],
and H3K9ac [21], cofactors (e.g. cohesion and mediator complex) and, chromatin-modifying molecules (e.g. p300). This
histone modification based data can provide the significant evidence in predicting active enhancers. In general there
are two types of enhancers: (1) Signal-dependent or inducible enhancers and (2) cell type-specific enhancers. The latter
cover the majority of all enhancers present in the genome.
As all human cell types can possess the same genome, cell-type specific enhancers are an important factor to deter-
mine cell-type specific gene expression programming. The mammalian genome contains millions of enhancers but
only a small number of enhancers are active in each cell type and the activity of enhancers is specific to its targeted
gene [22]. The term super-enhancers (Fig. 5) used to represent the active enhancer clusters that are present in a high
abundance in a specific genomic region [48]. These enhancers mainly regulate genes that are important for determin-
ing the cell identity. Therefore, enhancers provide the basis of cell identity and mutations in these enhancer regions can
cause abnormal cell growth and cause several diseases. The fluctuations in DNA methylation are also a cause of cancer
development and can directly affect the activity of the enhancers [40]. Furthermore, mutations in regulatory regions
of oncogenes can show a major impact in causing brain tumours [4]. In glioblastoma, EGFR amplification is linked with
the remodelled enhancer landscapes through the synthesis of FOXG1 and SOX9-dependent transcriptional factors.
This signature is highly sensitive to small molecules that disrupt H3K27ac inhibitors. H3K27ac is a histone modification
that plays a key role in the epigenetic regulation that controls the gene transcription, enhancer activity and chromatin
structure. EGFR amplification in glioblastoma is highly sensitive to small molecules that disrupt H3K27ac inhibitors and

Fig. 4  Enhancers are the non-regulatory elements of DNA. They can make 3D contact with other non-regulatory elements of DNA and are
bound by transcription factor proteins to control gene expression [31]

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Fig. 5  Systematic representation of typical and super-enhancers

activate an oncogenic gene expression program. This results in the activation of repetive element expression including
an endogenous retroviral element [37]. Furthermore, SMARCBI is the core subunit of SWI/SNF chromatin remodelling
that is lost in cancer which is responsible for maintaining the SWI/SNF complexes and it may result in the disruption of
the enhancer-mediated region of genes necessary for cell differentiation [].
Thandapani [43] reported that H3K4me1 histone modification of enhancers is catalyzed by MLL3/MLL4. In various
cancer types, MLL3 and MLL4 are mutated, which can reduce the amount of H3K4me1 on enhancers and prevent binding
of the mediator complex to those enhancers. MLL4 loss impaired the super-enhancer in lung cancers for the tumour sup-
pressor PER2 gene. Mutation in MLL3 and MLL4 can also lead to therapeutic resistance and dysregulation of enhancers
in various cancers. Therefore, a deep understanding of enhancer patterns can help reveal novel activation mechanisms
oncogenes in cancers.

4 Challenges for enhancer prediction

Enhancers are regions of DNA that are responsible for the transcription of one or more genes [46]. The position of enhanc-
ers is variable and relative to their target and can occur downstream, upstream, or within the introns of a gene. Enhancers
may make 3D contact with promoters to achieve regulation of distal genes [23]. Furthermore, there is no specific motif
or code for enhancers, and they may only be active in specific temporal, environmental, and spatial conditions [3]. These
characteristics of enhancers make it difficult to identify and annotate the enhancers. The experimental approaches for the
identification of enhancers fail to provide a complete list of active enhancers and do not help researchers to understand
why certain DNA regions act as enhancers and others do not [5].

5 Explainable Artificial Intelligence (XAI)

Explainable Artificial Intelligence (XAI) is an emerging and necessary field of artificial intelligence, particularly in the field
of healthcare, XAI, is designed to enhance human trust in artificial intelligence models by providing the explainability of
the model that how a specific model has been generated, and explaining the results of respective models to allow the
better understanding of the problem statement. Therefore, it helps the user to improve performance of the model and
provide more application domains. Hagras [19] explains the main important features of XAI including (1) Transparency: It
is right to describe how a decision has been made as it affects people’s lives, and the explanation should be in a human-
understandable format and language. (2) Causality: Does the model provide a complete explanation of the underlying
phenomena while providing the correct inferences from the data? (3) Bias: The AI models are trained on the dataset that
is coming from the real world, so how can we be sure that these models are also incorporating the biases? (4) Fairness:
Can we able to make sure that the decisions that are made by the AI systems are fair? And (5) Safety: Without a depth
understanding of the data how can we rely on AI models? A potential XAI system should be able to incorporate all the
mentioned features to provide complete transparency to the user.

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Hagras [19] also mentions the existing three main approaches to creating an XAI system. The first one is the deep
explanation which modifies the deep learning models’ techniques to understand explainable structures. A few exam-
ples include deepLIFT [39] and layer-wise relevance propagation [7]. The second approach is interpretable models:
this is an approach to interpret casual models or learn structures that can be applied to the graphical models, i.e.
Hidden Markov Model (HMM), statistical models such as naïve Bayes, logistic regression or random forest. However,
the output of these techniques is only understandable by experts and not by laymen. The last approach is the Model
Induction: which can be used to interpret the model from any opaque box models. Hagras [19] also mentioned that
the best approach to provide the explainability to users is by providing them the IF–THEN rules along with the linguis-
tic labels which can explain model output. Fuzzy logic systems (FLS) are one of the AI technique that provide IF-THEN
rules and linguistic labels AI model architecture shown in Fig. 6. FLS has 4 main components 1) Fuzzifier: this converts
crisp input into fuzzy sets. 2) Inference: This component generates the ideal rules for respective inputs. 3) Rule base:
it contains the membership functions and rules that control or regulate the decision-making process in a fuzzy logic
system. The rules are saved here in the form of IF-THEN conditions. And 4) Defuzzification: It transforms the fuzzy set
outputs into crisp outputs. An FLS directly converts the real number measurements into linguistic labels. They may
take the form of good, fair, bad; high, medium, low, or various combinations of the descriptive variables. Then these
linguistic labels are used to define the if–then rule base for describing the situation in a form that is explainable and
understandable. An example of a fuzzy rule may be “IF the tumour size is large and the homogeneity is high between
the cells THEN the patient has a malignant tumour”, here the linguistic labels are large, high, and malignant. It is very
simple for any individual, independent of their expertise, to understand what is being measured in the situation
and what will be the output. There are two main types of fuzzy logic systems Type-1 FLS and Type-2 FLS. The main
distinction between Type-1 FLS and Type-2 FLS is that Type-1 FLS are unable to directly handle the uncertainties
because of the specific nature of the membership functions. Type-1 FLS takes the input measured in real numbers
also called crisp inputs in terms of fuzzy logic system and fuzzifiers these values into fuzzy sets in the fuzzifier block.
After fuzzifying the inputs, the input fuzzy sets map onto the output fuzzy sets by using the fuzzy rules fired in the
inference box. Figure 7 represents the Type-1 fuzzy logic membership functions for the decision-making process of
early breast cancer detection. Sizilio et al., [40] took two input features (1) tumour area (range: 185–4255) and (2)
homogeneity range [0.01–0.45], and the outputs would be either benign (non-cancerous tumour) range [0–0.5],
malignant (cancerous tumour) range [0.6–1] or undefined range [0.5–0.6]. In the Type-2 fuzzy logic system instead
of defining the crisp membership functions, the fuzzy set includes another representation layer in the form of a

Fig. 6  Systematic Architecture of Fuzzy Logic System (FLS).

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Fig. 7  Representation of the tumour area (smaller and larger), tumour homogeneity (more and less) inputs and Benign, malignant, and
undefined output membership functions [36]

footprint of uncertainty (FOU) around the membership functions, which provides the additional degree of freedom
to handle the uncertainties [1, 34]. Type-2 inference fuzzy system structure is shown in Fig. 8.

Fig. 8  An overview of the Type-2 Fuzzy Logic System Operation

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6 Opaque box AI v/s explainable rule‑based models

It is challenging to understand the prediction of the opaque box model (e.g., deep learning) where the cumulative model
complexity can be used to achieve high prediction accuracies by these models. Alternatively, interpretable models can
provide a better understanding of how predictions have been made. To achieve transparency in the model a concept
of explainable AI has been proposed that explains the whole process of the model, i.e. the underlying procedure for
explaining the methods, procedures and output of the model that should be understandable by any human [28, 35]. A
comparison of the opaque box model and the XAI model is shown in Fig. 9.
The Rule-based explainable AI (XAI) model that generates the natural language IF/THEN rules as a classification algo-
rithm based on type 2 fuzzy logic, generates, integrates, and tests rules for accuracy and validity. This XAI model can help
the user to understand which rules are used by the classifier in making the prediction. Rule-based explainable AI (XAI)
is a class of artificial intelligence that explain the rule and insights into how AI-based system can make predictions and
decisions. XAI can explore the reasoning behind the process of decision-making and provide details on how the system
will work in the future and the system’s advantages and drawbacks [19]. XAI allows researchers to understand the insights
of the predicted results. Opaque-box models like a neural network, random forest and deep learning can always create
confusion like “How does the system predict the result”, “How does the model work”, “Are the results correct”, and “How
do overcome the errors”, “is the result trustworthy”. The use of XAI systems can overcome this confusion and provide a
clear and transparent prediction with explainable rules[44].

7 Computational methods used for the prediction of cancer

Cancer is a multifaceted and complex disease that continues to be a major healthcare challenge worldwide. Accurate
prediction and early detection of cancer are critical but at the same time important for reducing the burden of this dis-
ease. In recent years, the advancement in the field of machine learning and artificial intelligence has shown promising
results in early detection, diagnosis, and treatment of various cancers. Ström [41] reported that AI in combination with
cancer screening methods that include biopsy examination can increase the success rate of breast cancer treatment.
Computational radiology uses AI techniques such as computer vision, pattern recognition or lesion detection for the
classification of lesions according to Breast Imaging Reporting and Data System (BIRADS) and systematic diagnosis report-
ing. Mavaddat et al. [25] reported a genetic variant model that calculates the polygenic risk score to estimate the breast
cancer risk in a patient. Bakas et al. [8] have proposed a deep convolutional neural network AI-based model that uses
magnetic resonance imaging (MRI) data as input and generates rapid and accurate 3D segmentation of glioblastoma.
However, the MRI data failed to generate accurate results. Zhou et al. [50] proposed a support vector machine risk model

Fig. 9  Comparison between opaque box models and Explainable artificial intelligence

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that uses both clinical and genetic data, for predicting ovarian cancer. Mehrotra et al. [27], reported a deep learning-
based AI model for the classification of brain tumours. The model is trained on the Magnetic Resonance Imaging (MRI)
dataset, and it helps in the classification of both malignant and benign tumour cells. The model achieved an accuracy of
99.04%. Wankhede and Selvarani [47] published an MLL-CNN (multilevel layer model R-CNN) that is based on a relative
description model and feature weight factor-based feature selection strategy for the classification of the brain cancer.
They trained their model on MRI images to predict the glioblastoma. The model achieves an accuracy of 89%, specificity
of 97% and sensitivity of 98%. Toumazis et al. [45] uses the Bayesian model to detect lung cancer based on various risk
factors such as smoking exposure, genetics, and age.
However, where the machine learning and Deep learning-based model achieves higher accuracy, these techniques
are unable to explain how a particular result has been classified by a specific model. To resolve this issue, Gaur et al. [17]
proposed a new model that uses eXplainable AI modelling techniques for the prediction of brain tumours. XAI techniques
allow the model to make decisions based on certain rules, that ultimately help researchers or scientists to easily trace
results. The study uses the MRI image data for prediction and achieves an accuracy of 94.64%. However, there are still
gaps which need to be filled and there is a necessity to develop a molecular level-based feature set for the identification
of the real cause of the diseases and their accurate prediction.

8 Enhancers predictions methods

There are numerous experimental techniques used for the identification of enhancers. The first technique is transcription
factor binding site mapping onto the genome using ChIP-seq data [38]. The second technique is the use of epigenetic
markers (i.e., H3K27ac and H3K4me1) to identify active enhancers. The third approach is the identification of binding sites
of the histone acyltransferase EP300, a transcription factor protein that is required for the acetylation of nucleosomes and
is recruited by other TFs (Lee & Young [23]). In this approach, the histone modification data will be used to differentiate
the active and non-active enhancers [13]. Another approach for genome-wide identification of enhancers is STARR-seq
(Self-transcribing active regulatory region sequencing) a massively parallel reporter assay that allows the identification
of the enhancers based on the genome-wide activity and provides a quantitative measure of each region in the genome
to act as an enhancer and its activity [5].
Computational tools, specifically machine learning tools, are taking the lead in the identification of genome-wide
enhancers [36]. These tools use histone modification and high-throughput sequencing assay data as a training data set
and based on the extracted features predict the enhancers in genomes. Machine learning methods suffer from biases
and tend to predict promoters as enhancers [20]. Promoters are the upstream of Transcription Start Site that define
where the RNA polymerase begins the gene transcription [24]. Machine learning methods such as neural networks give
high enhancers prediction accuracy, however, they fail to explain the rules and insights through which the algorithm is
making the prediction [9]. Additionally, neural networks require large amounts of data as a training set [33].
A accurate prediction of enhancers is necessary to understand the role of non-regulatory genome regions in the con-
text of disease. Wolfe et al. [49] developed a Ruled-based explainable (XAI) model for the identification of the enhancers in
Drosophila melanogaster cell lines. The model was trained on histone modification ChIP-seq data of histone modifications
and STARR-seq data. For evaluating model performance, the XAI model was compared with traditional machine learning
models for enhancer prediction and annotation. Using this approach, the machine learning model was trained on the
same histone modification data as an explainable model, that accurately predicts enhancer locations and generalises to
other cell lines without adjustment. The project was based on the following aims: (1) Train the XAI model on the histone
modification ChIP-seq data. (2) Defining, interpreting, and implementing the rules for prediction of the XAI model, and
(3) Using this model to predict change in enhancers in other developmental, physiological or disease contexts. A com-
parison of the opaque box model and the XAI model used for enhancer prediction is shown in Fig. 10.

9 Why explainability is needed

The scientific community is working with a large amount of genomic data, and the focus has shifted to understanding
it fully and making it useable for the healthcare sector. The alteration in genomic region of living organisms can cause
numerous diseases. Multiple machine learning tools based on neural networks, deep learning and random forests have
been developed and have gained high accuracy and efficiency, but these tools lack explainability in their prediction

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Fig. 10  Comparison of opaque box model and XAI model. Both models are trained on genomic data, The opaque models give non-tracea-
ble predictions compared to XAI, which provides predictions along with the IF–THEN rule base that is understandable to layman

results. However, for the genomic scientific community, there is a need to develop explainable generalized models that
will help researchers understand the prediction and replicate them clinically to speed up traditional experimental meth-
ods aiming to develop new drugs, personalised therapies or propose new treatments and cures for diseases. Therefore,
there is a need to offer models that guarantee explainability and transparency in their prediction that will be understand-
able to a layman which can pave the way to developing predictions quickly to help improve disease outcomes, such as
with cancer, through personalized medicines.

Acknowledgements This work was supported by University of Essex (PhD scholarships to K.M). N.R.Z. was supported by Queen Mary University
of London. We would like to thank Ines Hofer for comments on the manuscript.

Author contributions K.M., H.H., and N.R.Z. conceived, designed and wrote the paper. The authors read and approved the final manuscript.

Data availability No datasets were generated or analysed during the current study.

Declarations
Competing interests The authors declare no competing interests.

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