Role of centromeres in evolution and karyotype diversity in Candida auris

Dr. Aswathy Narayanan’s interview with Bio Patrika hosting “Vigyaan Patrika”, a series of author interviews. Dr. Narayanan pursued her doctoral research in yeast genetics, under the guidance of Dr. Md. Anaul Kabir in National Institute of Technology Calicut, Kerala. Her doctoral research was focused on the eukaryotic protein folding machinery – its functions and interactome that are conserved across species. She joined Prof. Kaustuv Sanyal’s group in Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) as a postdoctoral researcher in 2016. Incidentally, around the same time, Candida auris emerged as a fungal pathogen of concern worldwide. Under Prof. Sanyal’s mentorship, she shifted her model organism from the docile Saccharomyces cerevisiae to the multidrug-resistant superbug C. auris. She is interested in multidrug resistance, stress response pathways, and karyotype evolution in fungal pathogens and aspires to identify pathogen-specific pathways/genes which can be translated to clinical practice in the future. She currently works as Scientist-B in a multicentre project funded by Indian Council of Medical Research involving JNCASR, Post Graduate Institute of Medical Education & Research (PGIMER) and Amity University Haryana. Outside the lab, she divides her time between music, books, and her three dogs. Here, Aswathy talks about her work on Functional and comparative analysis of centromeres reveals clade-Specific genome rearrangements in Candida auris and a chromosome number change in related species published in mBio.

Listen audio

How would you explain your paper’s key results to the non-scientific community?

Fungal pathogens cause infections in immunocompromised patients especially in intensive care units of hospitals. In 2009, Candida auris, a novel fungal pathogen was isolated in Japan. Within a decade, it was isolated from patients in hospitals in different parts of the world, and it is difficult to identify, treat and eradicate, as it is resistant to major antifungals used in clinics. Interestingly, C. auris isolated in different parts of the world exhibit different properties – they are grouped as clades based on their geographical isolation.

Fungal pathogens can alter their genomic content that helps them to adapt to different environmental and host niches. Previous studies from our lab have shown that most of these events include centromeres – the regions on the chromosome that facilitate the distribution of the genome content equally to the daughter cells during cell division. There are previous reports of the C. auris genome being dynamic. What are the properties of centromeres in C. auris? Are they different in the geographical clades and do they play any role in this diversity observed within a species? These are a few questions that intrigued us.

The first step was to identify the location of centromeres on the chromosomes. We tagged a histone protein that localizes specifically to the centromeres. Tracing its localization using chromatin immunoprecipitation and microscopy helped us to locate the centromere positions. We did these experiments in all geographical clades- and the centromeres had the same properties across clades. But, at the chromosome level, the analyses revealed interesting results. The East Asian clade, consisting of isolates mainly from Japan and Korea, had all chromosomes and centromere locations shuffled (1). This clade is the “odd-one-out”; they are sensitive to antifungals and are incapable of causing bloodstream infections.

Figure 1: Candida auris emerged as different geographical clades, out of which the East Asian clade (red) consists of atypical isolates that are drug-susceptible and incapable of causing invasive infections.

We then expanded the panel of our study and looked at a species complex closely related to C. auris, called Candida haemulonii complex. We identified centromeres in these species and found they had similar centromere properties, and gene neighborhoods. Though different species, they shared several patterns with C. auris – a centromere inactivation leading to a chromosome number change, chromosome breaks near centromeres – all hinted at the existence of a common ancestor shared by C. auris and C. haemulonii complex. Different species diverged from this ancestor and clade 2 diverged further, making it different from other clades.

Figure 2: Chromosome number variation in closely related species is mediated by a centromere inactivation event. Two centromeres placed on the same chromosome results in inactivation of one of the centromeres in a group of related species (highlighted in gray).

What are the possible consequences of these findings for your research area?

One of the observations of this study is that centromeres are genomic loci that evolve fast. So far, we knew this to be the case between species like C. albicans and C. dubliniensis (2). Now we know that the same is true within a species. This expands the notion of centromeres being just the primary constrictions involved in cell division. We uncover an instance of centromeres mediating chromosome number changes that is a major event in the emergence of a new species. It is tempting to consider centromeres as active participants in speciation.

We uncover an instance of centromeres mediating chromosome number changes that is a major event in the emergence of a new species.

What was the exciting moment (eureka moment) during your research?

The exciting moment was when we realized that two centromeres which were present on two different chromosomes in other related species were present on one chromosome in C. auris. This would imply that one of them must have been inactivated, as a chromosome can have only one functional centromere to be stable. We also know that sexual reproduction is responsible for the diversity we see in the living world. It was fascinating to think that nature has other raw materials for generating diversity in these asexual fungi and leaves some footprints of these events behind; we stumble upon them millions of years later.

What do you hope to do next?

Fungi are known for the chronic and persistent infections they cause. The fact that a fungal species emerged and spread across the whole globe within a short span is alarming- I would like to understand the factors that made this possible. We are familiar with fungal species like Candida albicans that grow at high temperatures; fortunately, we are armed with antifungals to combat these infections. We also know that some fungal species exist that are generally resistant to these antifungals, but the incidence of those infections is low. But C. auris is a species that has both the features- it can grow at high temperatures and exhibits resistance to antifungals which makes it a potential superbug. I plan to study the molecular mechanisms underlying these features.

Where do you seek scientific inspiration?

The fact that life originates and perfects itself under diverse conditions never fails to amuse me. It happens from deep waters to hot springs. Every living creature operates like a tiny unique machine – internally programmed and running for a time after which wear and tear sets in. During this process, it faces several adverse conditions and adapts persistently to stay alive. The intricacies of this regulation are a source of constant inspiration. Apart from this, Barbara McClintock, the scientist who was way ahead of her time, remains an inspiration.

How do you intend to help Indian science improve?

One aspect that the study on C. auris made me realize is that there are several endemic angles to a research question. We know that the Indian isolates of C. auris have properties of their own. I feel that microbiological research, especially when dealing with pathogens, can include these angles. This will help us to directly translate our understanding of molecular mechanisms to clinics- either as drug targets or diagnostics. I aim and hope to contribute to this aspect in the future.

References

1.        Narayanan A, Vadnala N, Ganguly P, Selvakumar P, Rudramurthy SM. 2021. Functional and comparative analysis of centromeres reveals clade-Specific genome rearrangements in Candida auris and a chromosome number change in related species. mBio 12:1–23.

2.        Padmanabhan S, Thakur J, Siddharthan R, Sanyal K. 2008. Rapid evolution of Cse4p-rich centromeric DNA sequences in closely related pathogenic yeasts, Candida albicans and Candida dubliniensis. Proc Natl Acad Sci U S A 105:19797–19802

Edited by: Anjali Mahilkar

Learn more about Prof. Kaustuv Sanyal’s research group here:

https://molecularmycologylab.wixsite.com/kaustuv

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: